Glucopyranoside compound

ABSTRACT

A compound of the formula: 
                         
wherein Ring A and Ring B are: (1) Ring A is an optionally substituted unsaturated monocyclic heterocyclic ring, and Ring B is an optionally substituted unsaturated monocyclic heterocyclic ring, an optionally substituted unsaturated fused heterobicyclic ring, or an optionally substituted benzene ring, (2) Ring A is an optionally substituted benzene ring, and Ring B is an optionally substituted unsaturated monocyclic heterocyclic ring or an optionally substituted unsaturated fused heterobicyclic ring, or (3) Ring A is an optionally substituted unsaturated fused heterobicyclic ring, and Ring B are independently an optionally substituted unsaturated monocyclic heterocyclic ring, an optionally substituted unsaturated fused heterobicyclic ring, or an optionally substituted benzene ring; X is a carbon atom or a nitrogen atom; Y is —(CH 2 ) n — (n is 1 or 2); or a pharmaceutically acceptable salt thereof, or a prodrug thereof.

TECHNICAL FIELD

This application is a Continuation of U.S. application Ser. No.13/174,814, filed Jul. 1, 2011, which is a Divisional of U.S.application Ser. No. 13/005,757, filed Jan. 13, 2011, which is aDivisional of U.S. application Ser. No. 11/045,446, filed Jan. 31, 2005,which issued as U.S. Pat. No. 7,943,788 B2 on May 17, 2011. U.S.application Ser. No. 11/045,446 is a Continuation-In-Part of PCTInternational Application No. PCT/JP2004/011312 filed on Jul. 30, 2004,which designated the United States and on which priority is claimedunder 35 U.S.C. §120, which claims priority of Provisional ApplicationNo. 60/491,534 filed on Aug. 1, 2003. The entire contents of each of theabove applications are hereby incorporated by reference.

BACKGROUND ART

Diet therapy and exercise therapy are essential in the treatment ofdiabetes mellitus. When these therapies do not sufficiently control theconditions of patients, insulin or an oral antidiabetic agent isadditionally used for the treatment of diabetes. At the present, therehave been used as an antidiabetic agent biguanide compounds,sulfonylurea compounds, insulin resistance improving agents andα-glucosidase inhibitors. However, these antidiabetic agents havevarious side effects. For example, biguanide compounds cause lacticacidosis, sulfonylurea compounds cause significant hypoglycemia, insulinresistance improving agents cause edema and heart failure, andα-glucosidase inhibitors cause abdominal bloating and diarrhea. Undersuch circumstances, it has been desired to develop novel drugs fortreatment of diabetes mellitus having no such side effects.

Recently, it has been reported that hyperglycemia participates in theonset and progressive impairment of diabetes mellitus, i.e., glucosetoxicity theory. Namely, chronic hyperglycemia leads to decrease ofinsulin secretion and further to decrease of insulin sensitivity, and asa result, the blood glucose concentration is increased so that diabetesmellitus is self-exacerbated [cf., Diabetologia, vol. 28, p. 119 (1985);Diabetes Care, vol. 13, p. 610 (1990), etc.]. Therefore, by treatinghyperglycemia, the aforementioned self-exacerbating cycle is interruptedso that the prophylaxis or treatment of diabetes mellitus is madepossible.

As one of the methods for treating hyperglycemia, it is considered toexcrete an excess amount of glucose directly into urine so that theblood glucose concentration is normalized. For example, by inhibitingsodium-dependent glucose transporter being present at the proximalconvoluted tubule of kidney, the re-absorption of glucose at the kidneyis inhibited, by which the excretion of glucose into urine is promotedso that the blood glucose level is decreased. In fact, it is confirmedthat by continuous subcutaneous administration of phlorizin having SGLTinhibitory activity to diabetic animal models, hyperglycemia isnormalized and the blood glucose level thereof can be kept normal for along time so that the insulin secretion and insulin resistance areimproved [cf., Journal of Clinical Investigation, vol. 79, p. 1510(1987); ibid., vol. 80, p. 1037 (1987); ibid., vol. 87, p. 561 (1991),etc.].

In addition, by treating diabetic animal models with SGLT inhibitoryagents for a long time, insulin secretion response and insulinsensitivity of the animals are improved without incurring any adverseaffects on the kidney or imbalance in blood levels of electrolytes, andas a result, the onset and progress of diabetic nephropathy and diabeticneuropathy are prevented [cf., Journal of Medicinal Chemistry, vol. 42,p. 5311 (1999); British Journal of Pharmacology, vol. 132, p. 578(2001), Ueta, Ishihara, Matsumoto, Oku, Nawano, Fujita, Saito, Arakawa,Life Sci., in press (2005), etc.].

From the above, SGLT inhibitors may be expected to improve insulinsecretion and insulin resistance by decreasing the blood glucose levelin diabetic patients and further prevent the onset and progress ofdiabetes mellitus and diabetic complications.

WO 01/27128 discloses an aryl C-glycoside compound having the followingstructure.

This compound is disclosed to be useful in the prophylaxis or treatmentof diabetes mellitus, etc., as an SGLT inhibitor.

DISCLOSURE OF INVENTION

The present invention relates to a compound of the following formula I,or a pharmaceutically acceptable salt thereof, or a prodrug thereof:

wherein Ring A and Ring B are one of the followings: (1) Ring A is anoptionally substituted unsaturated monocyclic heterocyclic ring, andRing B is an optionally substituted unsaturated monocyclic heterocyclicring, an optionally substituted unsaturated fused heterobicyclic ring,or an optionally substituted benzene ring, (2) Ring A is an optionallysubstituted benzene ring, and Ring B is an optionally substitutedunsaturated monocyclic heterocyclic ring, or an optionally substitutedunsaturated fused heterobicyclic ring wherein Y is linked to theheterocyclic ring of the fused heterobicyclic ring, or (3) Ring A is anoptionally substituted unsaturated fused heterobicyclic ring, whereinthe sugar moiety X-(sugar) and the moiety —Y— (Ring B) are both on thesame heterocyclic ring of the fused heterobicyclic ring, and Ring B isan optionally substituted unsaturated monocyclic heterocyclic ring, anoptionally substituted unsaturated fused heterobicyclic ring, or anoptionally substituted benzene ring;

X is a carbon atom or a nitrogen atom; and

Y is —(CH₂)_(n)— (wherein n is 1 or 2).

The compound of the formula I exhibits an inhibitory activity againstsodium-dependent glucose transporter being present in the intestine andthe kidney of mammalian species, and is useful in the treatment ofdiabetes mellitus or diabetic complications such as diabeticretinopathy, diabetic neuropathy, diabetic nephropathy, obesity, anddelayed wound healing.

BEST MODE FOR CARRYING OUT THE INVENTION

Hereinafter, the present compound (I) is illustrated in more detail.

The definitions for each term used in the description of the presentinvention are listed below.

The term “halogen atom” or “halo” means chlorine, bromine, fluorine andiodine, and chlorine and fluorine are preferable.

The term “alkyl group” means a straight or branched saturated monovalenthydrocarbon chain having 1 to 12 carbon atoms. The straight chain orbranched chain alkyl group having 1 to 6 carbon atoms is preferable, andthe straight chain or branched chain alkyl group having 1 to 4 carbonatoms is more preferable. Examples thereof are methyl group, ethylgroup, propyl group, isopropyl group, butyl group, t-butyl group,isobutyl group, pentyl group, hexyl group, isohexyl group, heptyl group,4,4-dimethylpentyl group, octyl group, 2,2,4-trimethylpentyl group,nonyl group, decyl group, and various branched chain isomers thereof.Further, the alkyl group may optionally and independently be substitutedby 1 to 4 substituents as listed below, if necessary.

The term “alkylene group” or “alkylene” means a straight or brancheddivalent saturated hydrocarbon chain having 1 to 12 carbon atoms. Thestraight chain or branched chain alkylene group having 1 to 6 carbonatoms is preferable, and the straight chain or branched chain alkylenegroup having 1 to 4 carbon atoms is more preferable. Examples thereofare methylene group, ethylene group, propylene group, trimethylenegroup, etc. If necessary, the alkylene group may optionally besubstituted in the same manner as the above-mentioned “alkyl group”.

Where alkylene groups as defined above attach at two different carbonatoms of the benzene ring, they form an annelated five, six or sevenmembered carbocycle together with the carbon atoms to which they areattached, and may optionally be substituted by one or more substituentsdefined below.

The term “alkenyl group” means a straight or branched monovalenthydrocarbon chain having 2 to 12 carbon atoms and having at least onedouble bond. Preferable alkenyl group is a straight chain or branchedchain alkenyl group having 2 to 6 carbon atoms, and the straight chainor branched chain alkenyl group having 2 to 4 carbon atoms is morepreferable. Examples thereof are vinyl group, 2-propenyl group,3-butenyl group, 2-butenyl group, 4-pentenyl group, 3-pentenyl group,2-hexenyl group, 3-hexenyl group, 2-heptenyl group, 3-heptenyl group,4-heptenyl group, 3-octenyl group, 3-nonenyl group, 4-decenyl group,3-undecenyl group, 4-dodecenyl group, 4,8,12-tetradecatrienyl group,etc. The alkenyl group may optionally and independently be substitutedby 1 to 4 substituents as mentioned below, if necessary.

The term “alkenylene group” means a straight or branched divalenthydrocarbon chain having 2 to 12 carbon atoms and having at least onedouble bond. The straight chain or branched chain alkenylene grouphaving 2 to 6 carbon atoms is preferable, and the straight chain orbranched chain alkenylene group having 2 to 4 carbon atoms is morepreferable. Examples thereof are vinylene group, propenylene group,butadienylene group, etc. If necessary, the alkylene group mayoptionally be substituted by 1 to 4 substituents as mentioned below, ifnecessary.

Where alkenylene groups as defined above attach at two different carbonatoms of the benzene ring, they form an annelated five, six or sevenmembered carbocycle (e.g., a fused benzene ring) together with thecarbon atoms to which they are attached, and may optionally besubstituted by one or more substituents defined below.

The term “alkynyl group” means a straight or branched monovalenthydrocarbon chain having at least one triple bond. The preferablealkynyl group is a straight chain or branched chain alkynyl group having2 to 6 carbon atoms, and the straight chain or branched chain alkynylgroup having 2 to 4 carbon atoms is more preferable. Examples thereofare 2-propynyl group, 3-butynyl group, 2-butynyl group, 4-pentynylgroup, 3-pentynyl group, 2-hexynyl group, 3-hexynyl group, 2-heptynylgroup, 3-heptynyl group, 4-heptynyl group, 3-octynyl group, 3-nonynylgroup, 4-decynyl group, 3-undecynyl group, 4-dodecynyl group, etc. Thealkynyl group may optionally and independently be substituted by 1 to 4substituents as mentioned below, if necessary.

The term “cycloalkyl group” means a monocyclic or bicyclic monovalentsaturated hydrocarbon ring having 3 to 12 carbon atoms, and themonocyclic saturated hydrocarbon group having 3 to 7 carbon atoms ismore preferable. Examples thereof are a monocyclic alkyl group and abicyclic alkyl group such as cyclopropyl group, cyclobutyl group,cyclopentyl group, cyclohexyl group, cycloheptyl group, cyclooctylgroup, cyclodecyl group, etc. These groups may optionally andindependently be substituted by 1 to 4 substituents as mentioned below,if necessary. The cycloalkyl group may optionally be condensed with asaturated hydrocarbon ring or an unsaturated hydrocarbon ring (saidsaturated hydrocarbon ring and unsaturated hydrocarbon ring mayoptionally contain an oxygen atom, a nitrogen atom, a sulfur atom, SO orSO₂ within the ring, if necessary), and the condensed saturatedhydrocarbon ring and the condensed unsaturated hydrocarbon ring may beoptionally and independently be substituted by 1 to 4 substituents asmentioned below.

The term “cycloalkylidene group” means a monocyclic or bicyclic divalentsaturated hydrocarbon ring having 3 to 12 carbon atoms, and themonocyclic saturated hydrocarbon group having 3 to 6 carbon atoms ispreferable. Examples thereof are a monocyclic alkylidene group and abicyclic alkylidene group such as cyclopropylidene group,cyclobutylidene group, cyclopentylidine group, cyclohexylidene group,etc. These groups may optionally and independently be substituted by 1to 4 substituents as mentioned below, if necessary. Besides, thecycloalkylidene group may optionally be condensed with a saturatedhydrocarbon ring or an unsaturated hydrocarbon ring (said saturatedhydrocarbon ring and unsaturated hydrocarbon ring may optionally containan oxygen atom, a nitrogen atom, a sulfur atom, SO or SO₂ within thering, if necessary), and the condensed saturated hydrocarbon ring andthe unsaturated hydrocarbon ring may be optionally and independently besubstituted by 1 to 4 substituents as mentioned below.

The term “cycloalkenyl group” means a monocyclic or bicyclic monovalentunsaturated hydrocarbon ring having 4 to 12 carbon atoms and having atleast one double bond. The preferable cycloalkenyl group is a monocyclicunsaturated hydrocarbon group having 4 to 7 carbon atoms. Examplesthereof are monocyclic alkenyl groups such as cyclopentenyl group,cyclopentadienyl group, cyclohexenyl group, etc. These groups mayoptionally and independently be substituted by 1 to 4 substituents asmentioned below, if necessary. Besides, the cycloalkenyl group mayoptionally be condensed with a saturated hydrocarbon ring or anunsaturated hydrocarbon ring (said saturated hydrocarbon ring andunsaturated hydrocarbon ring may optionally contain an oxygen atom, anitrogen atom, a sulfur atom, SO or SO₂ within the ring, if necessary),and the condensed saturated hydrocarbon ring and the unsaturatedhydrocarbon ring may be optionally and independently be substituted by 1to 4 substituents as mentioned below.

The term “cycloalkynyl group” means a monocyclic or bicyclic unsaturatedhydrocarbon ring having 6 to 12 carbon atoms, and having at least onetriple bond. The preferable cycloalkynyl group is a monocyclicunsaturated hydrocarbon group having 6 to 8 carbon atoms. Examplesthereof are monocyclic alkynyl groups such as cyclooctynyl group,cyclodecynyl group. These groups may optionally be substituted by 1 to 4substituents as mentioned below, if necessary. Besides, the cycloalkynylgroup may optionally and independently be condensed with a saturatedhydrocarbon ring or an unsaturated hydrocarbon ring (said saturatedhydrocarbon ring and unsaturated hydrocarbon ring may optionally containan oxygen atom, a nitrogen atom, a sulfur atom, SO or SO₂ within thering, if necessary), and the condensed saturated hydrocarbon ring or theunsaturated hydrocarbon ring may be optionally and independently besubstituted by 1 to 4 substituents as mentioned below.

The term “aryl group” means a monocyclic or bicyclic monovalent aromatichydrocarbon group having 6 to 10 carbon atoms. Examples thereof arephenyl group, naphthyl group (including 1-naphthyl group and 2-naphthylgroup). These groups may optionally and independently be substituted by1 to 4 substituents as mentioned below, if necessary. Besides, the arylgroup may optionally be condensed with a saturated hydrocarbon ring oran unsaturated hydrocarbon ring (said saturated hydrocarbon ring andunsaturated hydrocarbon ring may optionally contain an oxygen atom, anitrogen atom, a sulfur atom, SO or SO₂ within the ring, if necessary),and the condensed saturated hydrocarbon ring or the unsaturatedhydrocarbon ring may be optionally and independently be substituted by 1to 4 substituents as mentioned below.

The term “unsaturated monocyclic heterocyclic ring” means an unsaturatedhydrocarbon ring containing 1-4 heteroatoms independently selected froma nitrogen atom, an oxygen atom and a sulfur atom, and the preferableone is a 4- to 7-membered saturated or unsaturated hydrocarbon ringcontaining 1-4 heteroatoms independently selected from a nitrogen atom,an oxygen atom and a sulfur atom. Examples thereof are pyridine,pyrimidine, pyrazine, furan, thiophene, pyrrole, imidazole, pyrazole,oxazole, isoxazole, 4,5-dihydrooxazole, triazole, isothiazole,thiadiazole, triazole, tetrazole, etc. Among them, pyridine, pyrimidine,pyrazine, furan, thiophene, pyrrole, imidazole, oxazole, and thiazolecan be preferably used. The “unsaturated monocyclic heterocyclic ring”may optionally and independently be substituted by 1-4 substituents asmentioned below, if necessary.

The term “unsaturated fused heterobicyclic ring” means hydrocarbon ringcomprised of a saturated or a unsaturated hydrocarbon ring condensedwith the above mentioned unsaturated monocyclic heterocyclic ring wheresaid saturated hydrocarbon ring and said unsaturated hydrocarbon ringmay optionally contain an oxygen atom, a nitrogen atom, a sulfur atom,SO, or SO₂ within the ring, if necessary. The “unsaturated fusedheterobicyclic ring” includes, for example, benzothiophene, indole,tetrahydrobenzothiophene, benzofuran, isoquinoline, thienothiophene,thienopyridine, quinoline, indoline, isoindoline, benzothiazole,benzoxazole, indazole, dihydroisoquinoline, etc. Further, the“heterocyclic ring” also includes possible N- or S-oxides thereof.

The term “heterocyclyl” means a monovalent group of the above-mentionedunsaturated monocyclic heterocyclic ring or unsaturated fusedheterobicyclic ring and a monovalent group of the saturated version ofthe above-mentioned unsaturated monocyclic heterocyclic or unsaturatedfused heterobicyclic ring. If necessary, the heterocyclyl may optionallyand independently be substituted by 1 to 4 substituents as mentionedbelow.

The term “alkanoyl group” means a formyl group and ones formed bybinding an “alkyl group” to a carbonyl group.

The term “alkoxy group” means ones formed by binding an “alkyl group” toan oxygen atom.

The substituent for the above each group includes, for example, ahalogen atom (e.g., fluorine, chlorine, bromine, iodine), a nitro group,a cyano group, an oxo group, a hydroxy group, a mercapto group, acarboxyl group, a sulfo group, an alkyl group, an alkenyl group, analkynyl group, a cycloalkyl group, a cycloalkylidenemethyl group, acycloalkenyl group, a cycloalkynyl group, an aryl group, a heterocyclylgroup, an alkoxy group, an alkenyloxy group, an alkynyloxy group, acycloalkyloxy group, a cycloalkenyloxy group, a cycloalkynyloxy group,an aryloxy group, a heterocyclyloxy group, an alkanoyl group, analkenylcarbonyl group, an alkynylcarbonyl group, a cycloalkylcarbonylgroup, a cycloalkenylcarbonyl group, a cycloalkynylcarbonyl group, anarylcarbonyl group, a heterocyclylcarbonyl group, an alkoxycarbonylgroup, an alkenyloxycarbonyl group, an alkynyloxycarbonyl group, acycloalkyloxycarbonyl group, a cycloalkenyloxycarbonyl group, acycloalkynyloxycarbonyl group, an aryloxycarbonyl group, aheterocyclyloxycarbonyl group, an alkanoyloxy group, analkenylcarbonyloxy group, an alkynylcarbonyloxy group, acycloalkylcarbonyloxy group, a cycloalkenylcarbonyloxy group, acycloalkynylcarbonyloxy group, an arylcarbonyloxy group, aheterocyclylcarbonyloxy group, an alkylthio group, an alkenylthio group,an alkynylthio group, a cycloalkylthio group, a cycloalkenylthio group,a cycloalkynylthio group, an arylthio group, a heterocyclylthio group,an amino group, a mono- or di-alkylamino group, a mono- ordi-alkanoylamino group, a mono- or di-alkoxycarbonylamino group, a mono-or di-arylcarbonylamino group, an alkylsulfinylamino group, analkylsulfonylamino group, an arylsulfinylamino group, anarylsulfonylamino group, a carbamoyl group, a mono- or di-alkylcarbamoylgroup, a mono- or di-arylcarbamoyl group, an alkylsulfinyl group, analkenylsulfinyl group, an alkynylsulfinyl group, a cycloalkylsulfinylgroup, a cycloalkenylsulfinyl group, a cycloalkynylsulfinyl group, anarylsulfinyl group, a heterocyclylsulfinyl group, an alkylsulfonylgroup, an alkenylsulfonyl group, an alkynylsulfonyl group, acycloalkylsulfonyl group, a cycloalkenylsulfonyl group, acycloalkynylsulfonyl group, an arylsulfonyl group, and aheterocyclylsulfonyl group. Each group as mentioned above may optionallybe substituted by these substituents.

Further, the terms such as a haloalkyl group, a halo-lower alkyl group,a haloalkoxy group, a halo-lower alkoxy group, a halophenyl group, or ahaloheterocyclyl group mean an alkyl group, a lower alkyl group, analkoxy group, a lower alkoxy group, a phenyl group or a heterocyclylgroup (hereinafter, referred to as an alkyl group, etc.) beingsubstituted by one or more halogen atoms, respectively. Preferable onesare an alkyl group, etc. being substituted by 1 to 7 halogen atoms, andmore preferable ones are an alkyl group, etc. being substituted by 1 to5 halogen atoms. Similarly, the terms such as a hydroxyalkyl group, ahydroxy-lower alkyl group, a hydroxyalkoxy group, a hydroxy-lower alkoxygroup and a hydroxyphenyl group mean an alkyl group, etc., beingsubstituted by one or more hydroxy groups. Preferable ones are an alkylgroup, etc., being substituted by 1 to 4 hydroxy groups, and morepreferable ones are an alkyl group, etc., being substituted by 1 to 2hydroxy groups. Further, the terms such as an alkoxyalkyl group, a loweralkoxyalkyl group, an alkoxy-lower alkyl group, a lower alkoxy-loweralkyl group, an alkoxyalkoxy group, a lower alkoxyalkoxy group, analkoxy-lower alkoxy group, a lower alkoxy-lower alkoxy group, analkoxyphenyl group, and a lower alkoxyphenyl group means an alkyl group,etc., being substituted by one or more alkoxy groups. Preferable onesare an alkyl group, etc., being substituted by 1 to 4 alkoxy groups, andmore preferable ones are an alkyl group, etc., being substituted by 1 to2 alkoxy groups.

The terms “arylakyl” and “arylalkoxy” as used alone or as part ofanother group refer to alkyl and alkoxy groups as described above havingan aryl substituent.

The term “lower” used in the definitions for the formulae in the presentspecification means a straight or branched carbon chain having 1 to 6carbon atoms, unless defined otherwise. More preferably, it means astraight or branched carbon chain having 1 to 4 carbon atoms.

The term “prodrug” means an ester or carbonate, which is formed byreacting one or more hydroxy groups of the compound of the formula Iwith an acylating agent substituted by an alkyl, an alkoxy or an aryl bya conventional method to produce acetate, pivalate, methylcarbonate,benzoate, etc. Further, the prodrug includes also an ester or amide,which is similarly formed by reacting one or more hydroxy groups of thecompound of the formula I with an α-amino acid or a β-amino acid, etc.using a condensing agent by a conventional method.

The pharmaceutically acceptable salt of the compound of the formula Iincludes, for example, a salt with an alkali metal such as lithium,sodium, potassium, etc.; a salt with an alkaline earth metal such ascalcium, magnesium, etc.; a salt with zinc or aluminum; a salt with anorganic base such as ammonium, choline, diethanolamine, lysine,ethylenediamine, t-butylamine, t-octylamine,tris(hydroxymethyl)aminomethane, N-methyl glucosamine, triethanolamineand dehydroabietylamine; a salt with an inorganic acid such ashydrochloric acid, hydrobromic acid, hydroiodic acid, sulfuric acid,nitric acid, phosphoric acid, etc.; or a salt with an organic acid suchas formic acid, acetic acid, propionic acid, oxalic acid, malonic acid,succinic acid, fumaric acid, maleic acid, lactic acid, malic acid,tartaric acid, citric acid, methanesulfonic acid, ethanesulfonic acid,benzenesulfonic acid, etc.; or a salt with an acidic amino acid such asaspartic acid, glutamic acid, etc.

The compound of the present invention also includes a mixture ofstereoisomers, or each pure or substantially pure isomer. For example,the present compound may optionally have one or more asymmetric centersat a carbon atom containing any one of substituents. Therefore, thecompound of the formula I may exist in the form of enantiomer ordiastereomer, or a mixture thereof. When the present compound (I)contains a double bond, the present compound may exist in the form ofgeometric isomerism (cis-compound, trans-compound), and when the presentcompound (I) contains an unsaturated bond such as carbonyl, then thepresent compound may exist in the form of a tautomer, and the presentcompound also includes these isomers or a mixture thereof. The startingcompound in the form of a racemic mixture, enantiomer or diastereomermay be used in the processes for preparing the present compound. Whenthe present compound is obtained in the form of a diastereomer orenantiomer, they can be separated by a conventional method such aschromatography or fractional crystallization.

In addition, the present compound (I) includes an intramolecular salt,hydrate, solvate or polymorphism thereof.

Examples of the optionally substituted unsaturated monocyclicheterocyclic ring of the present invention include an unsaturatedmonocyclic heterocyclic ring which may optionally be substituted by 1-5substituents selected from the group consisting of a halogen atom, anitro group, a cyano group, an oxo group, a hydroxyl group, a mercaptogroup, a carboxyl group, a sulfo group, an alkyl group, an alkenylgroup, an alkynyl group, a cycloalkyl group, a cycloalkylidenemethylgroup, a cycloalkenyl group, a cycloalkynyl group, an aryl group, aheterocyclyl group, an alkoxy group, an alkenyloxy group, an alkynyloxygroup, a cycloalkyloxy group, a cycloalkenyloxy group, a cycloalkynyloxygroup, an aryloxy group, a heterocyclyloxy group, an alkanoyl group, analkenylcarbonyl group, an alkynylcarbonyl group, a cycloalkylcarbonylgroup, a cycloalkenylcarbonyl group, a cycloalkynylcarbonyl group, anarylcarbonyl group, a heterocyclylcarbonyl group, an alkoxycarbonylgroup, an alkenyloxycarbonyl group, an alkynyloxycarbonyl group, acycloalkyloxycarbonyl group, a cycloalkenyloxycarbonyl group, acycloalkynyloxycarbonyl group, an aryloxycarbonyl group, aheterocyclyloxycarbonyl group, an alkanoyloxy group, analkenylcarbonyloxy group, an alkynylcarbonyloxy group, acycloalkylcarbonyloxy group, a cycloalkenylcarbonyloxy group, acycloalkynylcarbonyloxy group, an arylcarbonyloxy group, aheterocyclylcarbonyloxy group, an alkylthio group, an alkenylthio group,an alkynylthio group, a cycloalkylthio group, a cycloalkenylthio group,a cycloalkynylthio group, an arylthio group, a heterocyclylthio group,an amino group, a mono- or di-alkylamino group, a mono- ordi-alkanoylamino group, a mono- or di-alkoxycarbonylamino group, a mono-or di-arylcarbonylamino group, an alkylsulfinylamino group, analkylsulfonylamino group, an arylsulfinylamino group, anarylsulfonylamino group, a carbamoyl group, a mono- or di-alkylcarbamoylgroup, a mono- or di-arylcarbamoyl group, an alkylsulfinyl group, analkenylsulfinyl group, an alkynylsulfinyl group, a cycloalkylsulfinylgroup, a cycloalkenylsulfinyl group, a cycloalkynylsulfinyl group, anarylsulfinyl group, a heterocyclylsulfinyl group, an alkylsulfonylgroup, an alkenylsulfonyl group, an alkynylsulfonyl group, acycloalkylsulfonyl group, a cycloalkenylsulfonyl group, acycloalkynylsulfonyl group, an arylsulfonyl group, and aheterocyclylsulfonyl group wherein each substituent may optionally befurther substituted by these substituents.

Examples of the optionally substituted unsaturated fused heterobicyclicring of the present invention include an unsaturated fusedheterobicyclic ring which may optionally be substituted by 1-5substituents selected from the group consisting of a halogen atom, anitro group, a cyano group, an oxo group, a hydroxy group, a mercaptogroup, a carboxyl group, a sulfo group, an alkyl group, an alkenylgroup, an alkynyl group, a cycloalkyl group, a cycloalkylidene-methylgroup, a cycloalkenyl group, a cycloalkynyl group, an aryl group, aheterocyclyl group, an alkoxy group, an alkenyloxy group, an alkynyloxygroup, a cycloalkyloxy group, a cycloalkenyloxy group, a cycloalkynyloxygroup, an aryloxy group, a heterocyclyloxy group, an alkanoyl group, analkenylcarbonyl group, an alkynylcarbonyl group, a cycloalkylcarbonylgroup, a cycloalkenyl-carbonyl group, a cycloalkynyl-carbonyl group, anarylcarbonyl group, a heterocyclylcarbonyl group, an alkoxycarbonylgroup, an alkenyloxycarbonyl group, an alkynyloxy-carbonyl group, acycloalkyloxycarbonyl group, a cycloalkenyloxy-carbonyl group, acycloalkynyloxycarbonyl group, an aryloxycarbonyl group, aheterocyclyloxycarbonyl group, an alkanoyloxy group, analkenylcarbonyloxy group, an alkynylcarbonyloxy group, acyclo-alkylcarbonyloxy group, a cycloalkenylcarbonyloxy group, acyclo-alkynylcarbonyloxy group, an arylcarbonyloxy group, aheterocyclyl-carbonyloxy group, an alkylthio group, an alkenylthiogroup, an alkynylthio group, a cycloalkylthio group, a cycloalkenylthiogroup, a cycloalkynylthio group, an arylthio group, a heterocyclylthiogroup, an amino group, a mono- or di-alkylamino group, a mono- ordi-alkanoyl-amino group, a mono- or di-alkoxycarbonylamino group, amono- or di-arylcarbonylamino group, an alkylsulfinylamino group, analkyl-sulfonylamino group, an arylsulfinylamino group, anarylsulfonylamino group, a carbamoyl group, a mono- or di-alkylcarbamoylgroup, a mono- or di-arylcarbamoyl group, an alkylsulfinyl group, analkenylsulfinyl group, an alkynylsulfinyl group, a cycloalkylsulfinylgroup, a cycloalkenylsulfinyl group, a cycloalkynylsulfinyl group, anarylsulfinyl group, a heterocyclylsulfinyl group, an alkylsulfonylgroup, an alkenylsulfonyl group, an alkynylsulfonyl group, acycloalkylsulfonyl group, a cycloalkenylsulfonyl group, acycloalkynylsulfonyl group, an arylsulfonyl group, and aheterocyclylsulfonyl group, wherein each substituent may optionally befurther substituted by these substituents.

Examples of the optionally substituted benzene ring of the presentinvention include a benzene ring which may optionally be substituted by1-5 substituents selected from the group consisting of a halogen atom, anitro group, a cyano group, a hydroxy group, a mercapto group, acarboxyl group, a sulfo group, an alkyl group, an alkenyl group, analkynyl group, a cycloalkyl group, a cycloalkylidenemethyl group, acycloalkenyl group, a cycloalkynyl group, an aryl group, a heterocyclylgroup, an alkoxy group, an alkenyloxy group, an alkynyloxy group, acycloalkyloxy group, a cycloalkenyloxy group, a cycloalkynyloxy group,an aryloxy group, a heterocyclyloxy group, an alkanoyl group, analkenylcarbonyl group, an alkynylcarbonyl group, a cycloalkylcarbonylgroup, a cycloalkenylcarbonyl group, a cycloalkynylcarbonyl group, anarylcarbonyl group, a heterocyclylcarbonyl group, an alkoxycarbonylgroup, an alkenyloxycarbonyl group, an alkynyloxycarbonyl group, acycloalkyloxycarbonyl group, a cycloalkenyloxycarbonyl group, acycloalkynyloxycarbonyl group, an aryloxycarbonyl group, aheterocyclyloxycarbonyl group, an alkanoyloxy group, analkenylcarbonyloxy group, an alkynylcarbonyloxy group, acycloalkylcarbonyloxy group, a cycloalkenylcarbonyloxy group, acycloalkynylcarbonyloxy group, an arylcarbonyloxy group, aheterocyclylcarbonyloxy group, an alkylthio group, an alkenylthio group,an alkynylthio group, a cycloalkylthio group, a cycloalkenylthio group,a cycloalkynylthio group, an arylthio group, a heterocyclylthio group,an amino group, a mono- or di-alkylamino group, a mono- ordi-alkanoylamino group, a mono- or di-alkoxycarbonylamino group, a mono-or di-arylcarbonylamino group, an alkylsulfinylamino group, analkylsulfonylamino group, an arylsulfinylamino group, anarylsulfonylamino group, a carbamoyl group, a mono- or di-alkylcarbamoylgroup, a mono- or di-arylcarbamoyl group, an alkylsulfinyl group, analkenylsulfinyl group, an alkynylsulfinyl group, a cycloalkylsulfinylgroup, a cycloalkenylsulfinyl group, a cycloalkynylsulfinyl group, anarylsulfinyl group, a heterocyclylsulfinyl group, an alkylsulfonylgroup, an alkenylsulfonyl group, an alkynylsulfonyl group, acycloalkylsulfonyl group, a cycloalkenylsulfonyl group, acycloalkynylsulfonyl group, an arylsulfonyl group, aheterocyclylsulfonyl group, an alkylene group, an alkyleneoxy group, analkylenedioxy group, and an alkenylene group wherein each substituentmay optionally be further substituted by these substituents. Moreover,examples of the optionally substituted benzene ring include a benzenering substituted with an alkylene group to form an annelated carbocycletogether with the carbon atoms to which they are attached, and alsoincludes a benzene ring substituted with an alkenylene group to form anannelated carbocycle such as a fused benzene ring together with thecarbon atoms to which they are attached.

Preferable examples of the optionally substituted unsaturated monocyclicheterocyclic ring include an unsaturated monocyclic heterocyclic ringwhich may optionally be substituted by 1-3 substituents selected fromthe group consisting of a halogen atom, a hydroxy group, an alkoxygroup, an alkyl group, a haloalkyl group, a haloalkoxy group, ahydroxyalkyl group, an alkoxyalkyl group, an alkoxyalkoxy group, analkenyl group, an alkynyl group, a cycloalkyl group, acycloalkylidenemethyl group, a cycloalkenyl group, a cycloalkyloxygroup, an aryl group, an aryloxy group, an arylalkoxy group, a cyanogroup, a nitro group, an amino group, a mono- or di-alkylamino group, analkanoylamino group, an alkoxycarbonylamino group, a carboxyl group, analkoxycarbonyl group, a carbamoyl group, a mono- or di-alkylcarbamoylgroup, an alkanoyl group, an alkylsulfonylamino group, anarylsulfonylamino group, an alkylsulfinyl group, an alkylsulfonyl group,an arylsulfonyl group, a heterocyclyl group, and an oxo group.

Preferable examples of the optionally substituted unsaturated fusedheterobicyclic ring include an unsaturated fused heterobicyclic ringwhich may optionally be substituted by 1-3 substituents independentlyselected from the group consisting of a halogen atom, a hydroxy group,an alkoxy group, an alkyl group, a haloalkyl group, a haloalkoxy group,a hydroxyalkyl group, an alkoxyalkyl group, an alkoxyalkoxy group, analkenyl group, an alkynyl group, a cycloalkyl group, acycloalkylidenemethyl group, a cycloalkenyl group, a cycloalkyloxygroup, an aryl group, an aryloxy group, an arylalkoxy group, a cyanogroup, a nitro group, an amino group, a mono- or di-alkylamino group, analkanoylamino group, an alkoxycarbonylamino group, a carboxyl group, analkoxycarbonyl group, a carbamoyl group, a mono- or di-alkylcarbamoylgroup, an alkanoyl group, an alkylsulfonylamino group, anarylsulfonylamino group, an alkylsulfinyl group, an alkylsulfonyl group,an arylsulfonyl group, a heterocyclyl group, and an oxo group.

Preferable examples of the optionally substituted benzene ring include abenzene ring which may optionally be substituted by 1-3 substituentsselected from the group consisting of a halogen atom, a hydroxy group,an alkoxy group, an alkyl group, a haloalkyl group, a haloalkoxy group,a hydroxyalkyl group, an alkoxyalkyl group, an alkoxyalkoxy group, analkenyl group, an alkynyl group, a cycloalkyl group, acycloalkylidenemethyl group, a cycloalkenyl group, a cycloalkyloxygroup, an aryl group, an aryloxy group, an arylalkoxy group, a cyanogroup, a nitro group, an amino group, a mono- or di-alkylamino group, analkanoylamino group, an alkoxycarbonylamino group, a carboxyl group, analkoxycarbonyl group, a carbamoyl group, a mono- or di-alkylcarbamoylgroup, an alkanoyl group, an alkylsulfonylamino group, anarylsulfonylamino group, an alkylsulfinyl group, an alkylsulfonyl group,an arylsulfonyl group, a heterocyclyl group, an alkylene group, analkyleneoxy group, an alkylenedioxy group, and an alkenylene group.

In another preferable embodiment of the present invention, theoptionally substituted unsaturated monocyclic heterocyclic ring is anunsaturated monocyclic heterocyclic ring which may optionally besubstituted by 1-3 substituents, independently selected from the groupconsisting of a halogen atom, a hydroxy group, a cyano group, a nitrogroup, an alkyl group, an alkenyl group, an alkynyl group, a cycloalkylgroup, a cycloalkylidenemethyl group, an alkoxy group, an alkanoylgroup, an alkylthio group, an alkylsulfonyl group, an alkylsulfinylgroup, an amino group, a mono- or di-alkylamino group, an alkanoylaminogroup, an alkoxycarbonylamino group, a sulfamoyl group, a mono- ordi-alkylsulfamoyl group, a carboxyl group, an alkoxycarbonyl group, acarbamoyl group, a mono- or di-alkylcarbamoyl group, analkylsulfonylamino group, a phenyl group, a phenoxy group, aphenylsulfonylamino group, a phenylsulfonyl group, a heterocyclyl group,and an oxo group;

the optionally substituted unsaturated fused heterobicyclic ring is anunsaturated fused heterobicyclic ring which may optionally besubstituted by 1-3 substituents selected from the group consisting of ahalogen atom, a hydroxy group, a cyano group, a nitro group, an alkylgroup, an alkenyl group, an alkynyl group, a cycloalkyl group, acycloalkylidenemethyl group, an alkoxy group, an alkylthio group, analkylsulfonyl group, an alkylsulfinyl group, an amino group, a mono- ordi-alkylamino group, an alkanoylamino group, an alkoxycarbonylaminogroup, a sulfamoyl group, a mono- or di-alkyl-sulfamoyl group, acarboxyl group, an alkoxycarbonyl group, a carbamoyl group, a mono- ordi-alkylcarbamoyl group, an alkanoyl group, an alkylsulfonylamino group,a phenyl group, a phenoxy group, a phenylsulfonylamino group,phenylsulfonyl group, a heterocyclyl group, and an oxo group; and

the optionally substituted benzene ring is a benzene ring which mayoptionally be substituted by 1-3 substituents, independently selectedfrom the group consisting of a halogen atom, a hydroxy group, a cyanogroup, a nitro group, an alkyl group, an alkenyl group, an alkynylgroup, a cycloalkyl group, a cycloalkylidenemethyl group, an alkoxygroup, an alkanoyl group, an alkylthio group, an alkylsulfonyl group, analklsulfinyl group, an amino group, a mono- or di-alkylamino group, analkanoylamino group, an alkoxycarbonylamino group, a sulfamoyl group, amono- or di-alkylsulfamoyl group, a carboxyl group, an alkoxycarbonylgroup, a carbamoyl group, a mono- or di-alkylcarbamoyl group, analkylsulfonylamino group, a phenyl group, a phenoxy group, aphenylsulfonylamino group, a phenylsulfonyl group, a heterocyclyl group,an alkylene group, and an alkenylene group;

wherein each of the above-mentioned substituents on the unsaturatedmonocyclic heterocyclic ring, the unsaturated fused heterobicyclic ringand the benzene ring may further be substituted by 1-3 substituents,independently selected from the group consisting of a halogen atom, ahydroxy group, a cyano group, an alkyl group, a haloalkyl group, analkoxy group, a haloalkoxy group, an alkanoyl group, an alkylthio group,an alkylsulfonyl group, a mono- or di-alkylamino group, a carboxylgroup, an alkoxycarbonyl group, a phenyl group, an alkyleneoxy group, analkylenedioxy group, an oxo group, a carbamoyl group, and a mono- ordi-alkylcarbamoyl group.

In a preferable embodiment, the optionally substituted unsaturatedmonocyclic heterocyclic ring is an unsaturated monocyclic heterocyclicring which may optionally be substituted by 1-3 substituents,independently selected from the group consisting of a halogen atom, acyano group, an alkyl group, an alkoxy group, an alkanoyl group, a mono-or di-alkylamino group, an alkanoylamino group, an alkoxycarbonylaminogroup, a carboxyl group, an alkoxycarbonyl group, a carbamoyl group, amono- or di-alkylcarbamoyl group, a phenyl group, a heterocyclyl group,and an oxo group;

the optionally substituted unsaturated fused heterobicyclic ring is anunsaturated fused heterobicyclic ring which may optionally besubstituted by 1-3 substituents independently selected from the groupconsisting of a halogen atom, a cyano group, an alkyl group, an alkoxygroup, an alkanoyl group, a mono- or di-alkylamino group, analkanoylamino group, an alkoxycarbonylamino group, a carboxy group, analkoxycarbonyl group, a carbamoyl group, a mono- or di-alkylcarbamoylgroup, a phenyl group, a heterocyclyl group, and an oxo group; and

the optionally substituted benzene ring is a benzene ring which mayoptionally be substituted by 1-3 substituents, independently selectedfrom the group consisting of a halogen atom, a cyano group, an alkylgroup, an alkoxy group, an alkanoyl group, a mono- or di-alkylaminogroup, an alkanoylamino group, an alkoxycarbonylamino group, a carboxylgroup, an alkoxycarbonyl group, a carbamoyl group, a mono- ordi-alkylcarbamoyl group, a phenyl group, a heterocyclyl group, analkylene group, and an alkenylene group;

wherein each of the above-mentioned substituents on the unsaturatedmonocyclic heterocyclic ring, the unsaturated fused heterobicyclic ringand the benzene ring may further be substituted by 1-3 substituents,independently selected from the group consisting of a halogen atom, acyano group, an alkyl group, a haloalkyl group, an alkoxy group, ahaloalkoxy group, an alkanoyl group, a mono- or di-alkylamino group, acarboxyl group, a hydroxy group, a phenyl group, an alkylenedioxy group,an alkyleneoxy group, an alkoxycarbonyl group, a carbamoyl group and amono- or di-alkylcarbamoyl group.

In another preferable embodiment,

(1) Ring A is an unsaturated monocyclic heterocyclic ring which mayoptionally be substituted by 1-3 substituents, independently selectedfrom the group consisting of a halogen atom, a hydroxy group, a cyanogroup, a nitro group, an alkyl group, an alkenyl group, an alkynylgroup, a cycloalkyl group, a cycloalkylidenemethyl group, an alkoxygroup, an alkanoyl group, an alkylthio group, an alkylsulfonyl group, analklsulfinyl group, an amino group, a mono- or di-alkylamino group, asulfamoyl group, a mono- or di-alkylsulfamoyl group, a carboxyl group,an alkoxycarbonyl group, a carbamoyl group, a mono- or di-alkylcarbamoylgroup, an alkylsulfonylamino group, a phenyl group, a phenoxy group, aphenylsulfonylamino group, a phenylsulfonyl group, a heterocyclyl group,and an oxo group, and

Ring B is an unsaturated monocyclic heterocyclic ring, an unsaturatedfused heterobicyclic ring, or a benzene ring, each of which mayoptionally be substituted by 1-3 substituents, independently selectedfrom the group consisting of a halogen atom, a hydroxy group, a cyanogroup, a nitro group, an alkyl group, an alkenyl group, an alkynylgroup, a cycloalkyl group, a cycloalkylidenemethyl group, an alkoxygroup, an alkanoyl group, an alkylthio group, an alkylsulfonyl group, analkylsulfinyl group, an amino group, a mono- or di-alkylamino group, asulfamoyl group, a mono- or di-alkylsulfamoyl group, a carboxyl group,an alkoxycarbonyl group, a carbamoyl group, a mono- or di-alkylcarbamoylgroup, an alkylsulfonylamino group, a phenyl group, a phenoxy group, aphenylsulfonylamino group, a phenylsulfonyl group, a heterocyclyl group,an alkylene group, and an alkenylene group;

(2) Ring A is a benzene ring which may optionally be substituted by 1-3substituents, independently selected from the group consisting of ahalogen atom, a hydroxy group, a cyano group, a nitro group, an alkylgroup, an alkenyl group, an alkynyl group, a cycloalkyl group, acycloalkylidenemethyl group, an alkoxy group, an alkanoyl group, analkylthio group, an alkylsulfonyl group, an alklsulfinyl group, an aminogroup, a mono- or di-alkylamino group, an alkanoylamino group, asulfamoyl group, a mono- or di-alkylsulfamoyl group, a carboxyl group,an alkoxycarbonyl group, a carbamoyl group, a mono- or di-alkylcarbamoylgroup, an alkylsulfonylamino group, a phenyl group, a phenoxy group, aphenylsulfonylamino group, a phenylsulfonyl group, a heterocyclyl group,an alkylene group, and an alkenylene group, and

Ring B is an unsaturated monocyclic heterocyclic ring or an unsaturatedfused heterobicyclic ring, each of which may optionally be substitutedby 1-3 substituents, independently selected from the group consisting ofa halogen atom, a hydroxy group, a cyano group, a nitro group, an alkylgroup, an alkenyl group, an alkynyl group, a cycloalkyl group, acycloalkylidenemethyl group, an alkoxy group, an alkanoyl group, analkylthio group, an alkylsulfonyl group, an alklsulfinyl group, an aminogroup, a mono- or di-alkylamino group, a sulfamoyl group, a mono- ordi-alkylsulfamoyl group, a carboxyl group, an alkoxycarbonyl group, acarbamoyl group, a mono- or di-alkylcarbamoyl group, analkylsulfonylamino group, a phenyl group, a phenoxy group, aphenylsulfonylamino group, a phenylsulfonyl group, a heterocyclyl group,an alkylene group and an oxo group; or

(3) Ring A is an unsaturated fused heterobicyclic ring which mayoptionally be substituted by 1-3 substituents, independently selectedfrom the group consisting of a halogen atom, a hydroxy group, a cyanogroup, a nitro group, an alkyl group, an alkenyl group, an alkynylgroup, a cycloalkyl group, a cycloalkylidenemethyl group, an alkoxygroup, an alkanoyl group, an alkylthio group, an alkylsulfonyl group, analklsulfinyl group, an amino group, a mono- or di-alkylamino group, asulfamoyl group, a mono- or di-alkylsulfamoyl group, a carboxyl group,an alkoxycarbonyl group, a carbamoyl group, a mono- or di-alkylcarbamoylgroup, an alkylsulfonylamino group, a phenyl group, a phenoxy group, aphenylsulfonylamino group, a phenylsulfonyl group, a heterocyclyl group,and an oxo group, and

Ring B is an unsaturated monocyclic heterocyclic ring, an unsaturatedfused heterobicyclic ring, or a benzene ring, each of which mayoptionally be substituted by 1-3 substituents, independently selectedfrom the group consisting of a halogen atom, a hydroxy group, a cyanogroup, a nitro group, an alkyl group, an alkenyl group, an alkynylgroup, a cycloalkyl group, a cycloalkylidenemethyl group, an alkoxygroup, an alkanoyl group, an alkylthio group, an alkylsulfonyl group, analklsulfinyl group, an amino group, a mono- or di-alkylamino group, asulfamoyl group, a mono- or di-alkylsulfamoyl group, a carboxyl group,an alkoxycarbonyl group, a carbamoyl group, a mono- or di-alkylcarbamoylgroup, an alkylsulfonylamino group, a phenyl group, a phenoxy group, aphenylsulfonylamino group, a phenylsulfonyl group, a heterocyclyl group,an alkylene group and an oxo group;

wherein each of the above-mentioned substituents on Ring A and Ring Bmay optionally be substituted by 1-3 substituents, independentlyselected from the group consisting of a halogen atom, a cyano group, analkyl group, a haloalkyl group, an alkoxy group, a haloalkoxy group, analkanoyl group, a mono- or di-alkylamino group, a carboxyl group, ahydroxy group, a phenyl group, an alkylenedioxy group, an alkyleneoxygroup, an alkoxycarbonyl group, a carbamoyl group and a mono- ordi-alkylcarbamoyl group.

In a more preferable embodiment of the present invention, Ring A andRing B are

(1) Ring A is an unsaturated monocyclic heterocyclic ring which mayoptionally be substituted by a halogen atom, a lower alkyl group, ahalo-lower alkyl group, a lower alkoxy group, or an oxo group, and RingB is (a) a benzene ring which may optionally be substituted by a halogenatom; a cyano group; a lower alkyl group; a halo-lower alkyl group; alower alkoxy group; a halo-lower alkoxy group; a mono- or di-loweralkylamino group; a phenyl group optionally substituted by a halogenatom, a cyano group, a lower alkyl group, a halo-lower alkyl group, alower alkoxy group, or a mono- or di-lower alkylamino group; or aheterocyclyl group optionally substituted by a halogen atom, a cyanogroup, a lower alkyl group, a halo-lower alkyl group, a lower alkoxygroup, or a mono- or di-lower alkylamino group; (b) an unsaturatedmonocyclic heterocyclic ring which may optionally be substituted by agroup selected from a halogen atom, cyano group, a lower alkyl group, ahalo-lower alkyl group, a lower alkoxy group, a halo-lower alkoxy group,a mo- or di-lower alkylamino group, a phenyl group which may besubstituted with a halogen atom, cyano group, a lower alkyl group, ahalo-lower alkyl group, a lower alkoxy group, or a mono- or di-loweralkylamino group; and a heterocyclyl group which may optionally besubstituted with a group selected from a halogen atom, cyano group, alower alkyl group, a halo-lower alkyl group, a lower alkoxy group, or amono- or di-lower alkylamino group; or (c) an unsaturated fusedheterobicyclic ring which may optionally be substituted by a groupselected from a halogen atom, cyano group, a lower alkyl group, ahalo-lower alkyl group, a lower alkoxy group, a halo-lower alkoxy group,a mono- or di-lower alkylamino group, a phenyl group which may besubstituted with a halogen atom, cyano group, a lower alkyl group, ahalo-lower alkyl group, a lower alkoxy group, or a mono- or di-loweralkylamino group; and a heterocyclyl group which may optionally besubstituted with a group selected from a halogen atom, cyano group, alower alkyl group, a halo-lower alkyl group, a lower alkoxy group, or amono- or di-lower alkylamino group;(2) Ring A is a benzene ring which may optionally be substituted by ahalogen atom, a lower alkyl group, a halo-lower alkyl group, a loweralkoxy group, a phenyl group, or a lower alkenylene group, and Ring B is(a) an unsaturated monocyclic heterocyclic ring which may optionally besubstituted by a halogen atom; a cyano group; a lower alkyl group; ahalo-lower alkyl group; a phenyl-lower alkyl group; a lower alkoxygroup; a halo-lower alkoxy group; a mono- or di-lower alkylamino group;a phenyl group optionally substituted by a halogen atom, a cyano group,a lower alkyl group, a halo-lower alkyl group, a lower alkoxy group, amono- or di-lower alkylamino group, or a carbamoyl group; or aheterocyclyl group optionally substituted by a halogen atom, a cyanogroup, a lower alkyl group, a halo-lower alkyl group, a lower alkoxygroup, a mono- or di-lower alkylamino group or a carbamoyl group; (b) anunsaturated fused heterobicyclic ring which may optionally besubstituted by a group selected from a halogen atom, cyano group, alower alkyl group, a halo-lower alkyl group, a phenyl-lower alkyl group,a lower alkoxy group, a halo-lower alkoxy group, a mo- or di-loweralkylamino group, a phenyl group which may be substituted with a halogenatom, cyano group, a lower alkyl group, a halo-lower alkyl group, alower alkoxy group, or a mono- or di-lower alkylamino group; and aheterocyclyl group which may optionally be substituted with a groupselected from a halogen atom, cyano group, a lower alkyl group, ahalo-lower alkyl group, a lower alkoxy group, or a mono- or di-loweralkylamino group; or(3) Ring A is an unsaturated fused heterobicyclic ring which mayoptionally be substituted by a halogen atom, a lower alkyl group, ahalo-lower alkyl group, a lower alkoxy group, or an oxo group, and RingB is (a) a benzene ring which may optionally be substituted by a groupselected from a halogen atom, cyano group, a lower alkyl group, ahalo-lower alkyl group, a lower alkoxy group, a halo-lower alkoxy group,a mo- or di-lower alkylamino group, a phenyl group which may besubstituted with a halogen atom, cyano group, a lower alkyl group, ahalo-lower alkyl group, a lower alkoxy group, or a mono- or di-loweralkylamino group; and a heterocyclyl group which may optionally besubstituted with a group selected from a halogen atom, cyano group, alower alkyl group, a halo-lower alkyl group, a lower alkoxy group, or amono- or di-lower alkylamino group; (b) an unsaturated monocyclicheterocyclic ring which may optionally be substituted by a halogen atom;a cyano group; a lower alkyl group; a halo-lower alkyl group; a loweralkoxy group; a halo-lower alkoxy group; a mono- or di-lower alkylaminogroup; a phenyl group optionally substituted by a halogen atom, a cyanogroup, a lower alkyl group, a halo-lower alkyl group, a lower alkoxygroup, or a mono- or di-lower alkylamino group; or a heterocyclyl groupoptionally substituted by a halogen atom, a cyano group, a lower alkylgroup, a halo-lower alkyl group, a lower alkoxy group, or a mono- ordi-lower alkylamino group; or (c) an unsaturated fused heterobicyclicring which may optionally be substituted by a group selected from ahalogen atom, cyano group, a lower alkyl group, a halo-lower alkylgroup, a lower alkoxy group, a halo-lower alkoxy group, a mo- ordi-lower alkylamino group, a phenyl group which may be substituted witha halogen atom, cyano group, a lower alkyl group, a halo-lower alkylgroup, a lower alkoxy group, or a mono- or di-lower alkylamino group;and a heterocyclyl group which may optionally be substituted with agroup selected from a halogen atom, cyano group, a lower alkyl group, ahalo-lower alkyl group, a lower alkoxy group, or a mono- or di-loweralkylamino group.

In another more preferable embodiment, Y is —CH₂— and is linked at the3-position of Ring A, with respect to X being the 1-position, Ring A isa benzene ring which is substituted by 1-3 substituents selected fromthe group consisting of a lower alkyl group, a halo-lower alkyl group, ahalogen atom, a lower alkoxy group, a phenyl group, and a loweralkenylene group, and Ring B is an unsaturated monocyclic heterocyclicring or an unsaturated fused heterobicyclic ring, each of which may besubstituted by 1-3 substituents selected from the group consisting of alower alkyl group, a halo-lower alkyl group, a phenyl-lower alkyl group,a halogen atom, a lower alkoxy group, a halo-lower alkoxy group, aphenyl group, a halophenyl group, a cyanophenyl group, a loweralkylphenyl group, a halo-lower alkylphenyl group, a lower alkoxyphenylgroup, a halo-lower alkoxy phenyl group, a lower alkylenedioxyphenylgroup, a lower alkyleneoxy phenyl group, a mono- or di-loweralkylaminophenyl group, a carbamoyl phenyl group, a mono- or di-loweralkylcarbamoylphenyl group, a heterocyclyl group, a haloheterocyclylgroup, a cyanoheterocyclyl group, a lower alkylheterocyclyl group, alower alkoxyheterocyclyl group, a mono- or di-loweralkylaminoheterocycyclyl group, a carbamoylheterocyclyl group, and amono- or di-lower alkylcarbamoyl group.

In another more preferable embodiment, Y is —CH₂— and is linked at the3-position of Ring A, with respect to X being the 1-position, Ring A isan unsaturated monocyclic heterocyclic ring which may be substituted by1-3 substituents selected from the group consisting of a lower alkylgroup, a halogen atom, a lower alkoxy group, and an oxo group, and RingB is a benzene ring which may be substituted by 1-3 substituentsselected from the group consisting of a lower alkyl group, a halo-loweralkyl group, a halogen atom, a lower alkoxy group, a halo-lower alkoxygroup, a phenyl group, a halophenyl group, a cyanophenyl group, a loweralkylphenyl group, a halo-lower alkylphenyl group, a lower alkoxyphenylgroup, a heterocyclyl group, a haloheterocyclyl group, acyanoheterocyclyl group, a lower alkylheterocyclyl group, and a loweralkoxyheterocyclyl group.

Further, in another preferable embodiment, Y is —CH₂— and is linked atthe 3-position of Ring A, with respect to X being the 1-position, Ring Ais an unsaturated monocyclic heterocyclic ring which may be substitutedby 1-3 substituents selected from the group consisting of a lower alkylgroup, a halogen atom, a lower alkoxy group, and an oxo group, and RingB is an unsaturated monocyclic heterocyclic ring or an unsaturated fusedheterobicyclic ring, each of which may be substituted by 1-3substituents selected from the group consisting of a lower alkyl group,a halo-lower alkyl group, a halogen atom, a lower alkoxy group, ahalo-lower alkoxy group, a phenyl group, a halophenyl group, acyanophenyl group, a lower alkylphenyl group, a halo-lower alkylphenylgroup, a lower alkoxyphenyl group, a halo-lower alkoxyphenyl group, aheterocyclyl group, a haloheterocyclyl group, a cyanoheterocyclyl group,a lower alkylheterocyclyl group, and a lower alkoxyheterocyclyl group.In a more preferable embodiment of the present invention, X is a carbonatom and Y is —CH₂—.

Further, in another preferable embodiment, Ring A and Ring B are

(1) Ring A is a benzene ring which may optionally be substituted by 1-3substituents, independently selected from the group consisting of ahalogen atom, a lower alkyl group optionally substituted by a halogenatom or a lower alkoxy group, a lower alkoxy group optionallysubstituted by a halogen atom or a lower alkoxy group, a cycloalkylgroup, a cycloalkoxy group, a phenyl group, and a lower alkenylenegroup, andRing B is an unsaturated monocyclic heterocyclic ring or an unsaturatedfused heterobicyclic ring, each of which may optionally be substitutedby 1-3 substituents, independently selected from the group consisting ofa halogen atom; a lower alkyl group optionally substituted by a halogenatom, a lower alkoxy group or a phenyl group; a lower alkoxy groupoptionally substituted by a halogen atom or a lower alkoxy group; acycloalkyl group; a cycloalkoxy group; a phenyl group optionallysubstituted by a halogen atom, a cyano group, a lower alkyl group, ahalo-lower alkyl group, a lower alkoxy group, a halo-lower alkoxy group,or a carbamoyl group; a heterocyclyl group optionally substituted by ahalogen atom, a cyano group, a lower alkyl group, a halo-lower alkylgroup, a lower alkoxy group, a halo-lower alkoxy group or a carbamoylgroup; and an oxo group,(2) Ring A is an unsaturated monocyclic heterocyclic ring which mayoptionally be substituted by 1-3 substituents, independently selectedfrom the group consisting of a halogen atom, a lower alkyl groupoptionally substituted by a lower alkoxy group, a lower alkoxy groupoptionally substituted by a halogen atom or a lower alkoxy group, acycloalkyl group, a cycloalkoxy group, and an oxo group, andRing B is a benzene ring which may optionally be substituted by 1-3substituents, independently selected from the group consisting of ahalogen atom; a lower alkyl group optionally substituted by a halogenatom, a lower alkoxy group or a phenyl group; a lower alkoxy groupoptionally substituted by a halogen atom or a lower alkoxy group; acycloalkyl group; a cycloalkoxy group; a phenyl group optionallysubstituted by a halogen atom, a cyano group, a lower alkyl group, ahalo-lower alkyl group, a lower alkoxy group or a halo-lower alkoxygroup; a heterocyclyl group optionally substituted by a halogen atom, acyano group, a lower alkyl group, a halo-lower alkyl group, a loweralkoxy group or a halo-lower alkoxy group; a lower alkylene group,(3) Ring A is an unsaturated monocyclic heterocyclic ring which mayoptionally be substituted by 1-3 substituents, independently selectedfrom the group consisting of a halogen atom, a lower alkyl groupoptionally substituted by a halogen atom or a lower alkoxy group, alower alkoxy group optionally substituted by a halogen atom or a loweralkoxy group, a cycloalkyl group, a cycloalkoxy group, and an oxo group,Ring B is an unsaturated monocyclic heterocyclic ring or an unsaturatedfused heterobicyclic ring, each of which may optionally be substitutedby 1-3 substituents, independently selected from the group consisting ofa halogen atom; a lower alkyl group optionally substituted by a halogenatom, a lower alkoxy group or a phenyl group; a lower alkoxy groupoptionally substituted by a halogen atom or a lower alkoxy group; acycloalkyl group; a cycloalkoxy group; a phenyl group optionallysubstituted by a halogen atom, a cyano group, a lower alkyl group, ahalo-lower alkyl group, a lower alkoxy group or a halo-lower alkoxygroup; a heterocyclyl group optionally substituted by a halogen atom, acyano group, a lower alkyl group, a halo-lower alkyl group, a loweralkoxy group or a halo-lower alkoxy group; and an oxo group;(4) Ring A is an unsaturated fused heterobicyclic ring which mayoptionally be substituted by 1-3 substituents, independently selectedfrom the group consisting of a halogen atom, a lower alkyl groupoptionally substituted by a lower alkoxy group, a lower alkoxy groupoptionally substituted by a halogen atom or a lower alkoxy group, acycloalkyl group, a cycloalkoxy group, and an oxo group,Ring B is a benzene ring which may optionally be substituted by 1-3substituents, independently selected from the group consisting of ahalogen atom; a lower alkyl group optionally substituted by a halogenatom, a lower alkoxy group or a phenyl group; a lower alkoxy groupoptionally substituted by a halogen atom or a lower alkoxy group; acycloalkyl group; a cycloalkoxy group; a phenyl group optionallysubstituted by a halogen atom, a cyano group, a lower alkyl group, ahalo-lower alkyl group, a lower alkoxy group or a halo-lower alkoxygroup; a heterocyclyl group optionally substituted by a halogen atom, acyano group, a lower alkyl group, a halo-lower alkyl group, a loweralkoxy group or a halo-lower alkoxy group; and a lower alkylene group,or(5) Ring A is an unsaturated monocyclic heterocyclic ring which mayoptionally be substituted by 1-3 substituents, independently selectedfrom the group consisting of a halogen atom, a lower alkyl groupoptionally substituted by a lower alkoxy group, a lower alkoxy groupoptionally substituted by a halogen atom or a lower alkoxy group, acycloalkyl group, a cycloalkoxy group, and an oxo group,Ring B is an unsaturated monocyclic heterocyclic ring or an unsaturatedfused heterobicyclic ring, each of which may optionally be substitutedby 1-3 substituents, independently selected from the group consisting ofa halogen atom; a lower alkyl group optionally substituted by a halogenatom, a lower alkoxy group or a phenyl group; a lower alkoxy groupoptionally substituted by a halogen atom or a lower alkoxy group; acycloalkyl group; a cycloalkoxy group; a phenyl group optionallysubstituted by a halogen atom, a cyano group, a lower alkyl group, ahalo-lower alkyl group, a lower alkoxy group or a halo-lower alkoxygroup; a heterocyclyl group optionally substituted by a halogen atom, acyano group, a lower alkyl group, a halo-lower alkyl group, a loweralkoxy group or a halo-lower alkoxy group; and an oxo group.

In another preferable embodiment of the present invention, Y is linkedat the 3-position of Ring A, with respect to X being the 1-position,Ring A is a benzene ring which may optionally be substituted by ahalogen atom, a lower alkyl group optionally substituted by a halogenatom, a lower alkoxy group, or a phenyl group, and Ring B is anunsaturated monocyclic heterocyclic ring or an unsaturated fusedheterobicyclic ring which may optionally be substituted by 1-3substituents, independently selected from the group consisting of ahalogen atom; a lower alkyl group optionally substituted by a halogenatom or a phenyl group; a lower alkoxy group; a phenyl group optionallysubstituted by a halogen atom, a cyano group, a lower alkyl group, ahalo-lower alkyl group, or a lower alkoxy group; a heterocyclyl groupoptionally substituted by a halogen atom, a cyano group, a lower alkylgroup, a halo-lower alkyl group, or a lower alkoxy group; and an oxogroup.

In another more preferable embodiment of the present invention, Y islinked at the 3-position of Ring A, with respect to X being the1-position, Ring A is an unsaturated monocyclic heterocyclic ring whichmay optionally be substituted by a substituent selected from a halogenatom, a lower alkyl group, and an oxo group, and Ring B is a benzenering which may optionally be substituted by a substituent selected fromthe group consisting of a halogen atom; a lower alkyl group optionallysubstituted by a halogen atom or a phenyl group; a lower alkoxy group; aphenyl group optionally substituted by a halogen atom, a cyano group, alower alkyl group, a halo-lower alkyl group, or a lower alkoxy group; aheterocyclyl group optionally substituted by a halogen atom, a cyanogroup, a lower alkyl group, a halo-lower alkyl group, or a lower alkoxygroup; and a lower alkylene group.

Preferable examples of unsaturated monocyclic heterocyclic ring includea 5- or 6-membered unsaturated heterocyclic ring containing 1 or 2hetero atoms independently selected from a nitrogen atom, an oxygenatom, and a sulfur atom. More specifically, preferred are furan,thiophene, oxazole, isoxazole, triazole, tetrazole, pyrazole, pyridine,pyrimidine, pyrazine, dihydroisoxazole, dihydropyridine, and triazole.Preferable unsaturated fused heterobicyclic ring includes a 9- or10-membered unsaturated fused heterocyclic ring containing 1 to 4 heteroatoms independently selected from a nitrogen atom, an oxygen atom, and asulfur atom. More specifically, preferred are indoline, isoindoline,benzothiazole, benzoxazole, indole, indazole, quinoline, isoquinoline,benzothiophene, benzofuran, thienothiophene, and dihydroisoquinoline.

In a more preferred embodiment of the present invention, Ring A is abenzene ring which may optionally be substituted by a substituentselected from the group consisting of a halogen atom, a lower alkylgroup, a halo-lower alkyl group, a lower alkoxy group, and a phenylgroup, and Ring B is a heterocyclic ring selected from the groupconsisting of thiophene, furan, benzofuran, benzothiophene, andbenzothiazole, wherein the heterocyclic ring may optionally besubstituted by a substituent selected from the following group: ahalogen atom, a cyano group, a lower alkyl group, a halo-lower alkylgroup, a phenyl-lower alkyl group, a lower alkoxy group, a halo-loweralkoxy group, a phenyl group, a halophenyl group, a lower alkylphenylgroup, a lower alkoxyphenyl group, a thienyl group, a halothienyl group,a pyridyl group, a halopyridyl group, and a thiazolyl group.

In yet another preferred embodiment, Y is —CH₂—, Ring A is anunsaturated monocyclic heterocyclic ring or an unsaturated fusedheterobicyclic ring selected from the group consisting of thiophene,dihydroisoquinoline, dihydroisoxazole, triazole, pyrazole,dihydropyridine, dihydroindole, indole, indazole, pyridine, pyrimidine,pyrazine, quinoline, and a isoindoline, wherein the heterocyclic ringmay optionally substituted by a substituent selected from the followinggroup: a halogen atom, a lower alkyl group, and an oxo group, and Ring Bis a benzene ring which may optionally be substituted by a substituentselected from the following group: a halogen atom, a lower alkyl group,a halo-lower alkyl group, a lower alkoxy group, and a halo-lower alkoxygroup.

In a further preferred embodiment of the present invention, Ring A is abenzene ring which is substituted by a halogen atom or a lower alkylgroup, and Ring B is thienyl group which is substituted by phenyl groupor a heterocyclyl group in which said phenyl group and heterocyclylgroup is substituted by 1-3 substituents selected from a halogen atom, acyano group, a lower alkyl group, a halo-lower alkyl group, a loweralkoxy group, and a halo-lower alkoxy group.

Further, in another aspect of the present invention, preferable examplesof the compound of the formula I include a compound wherein Ring A is

wherein R^(1a), R^(2a), R^(3a), R^(1b), R^(2b), and R^(3b) are eachindependently a hydrogen atom, a halogen atom, a hydroxy group, analkoxy group, an alkyl group, a haloalkyl group, a haloalkoxy group, ahydroxyalkyl group, an alkoxyalkyl group, an alkoxyalkoxy group, analkenyl group, an alkynyl group, a cycloalkyl group, acycloalkylidenemethyl group, a cycloalkenyl group, a cycloalkyloxygroup, a phenyl group, a phenylalkoxy group, a cyano group, a nitrogroup, an amino group, a mono- or di-alkylamino group, an alkanoylaminogroup, a carboxyl group, an alkoxycarbonyl group, a carbamoyl group, amono- or di-alkylcarbamoyl group, an alkanoyl group, analkylsulfonylamino group, a phenylsulfonylamino group, an alkylsulfinylgroup, an alkylsulfonyl group, or a phenylsulfonyl group, andRing B is

wherein R^(4a) and R^(5a) are each independently a hydrogen atom; ahalogen atom; a hydroxy group; an alkoxy group; an alkyl group; ahaloalkyl group; a haloalkoxy group; a hydroxyalkyl group; analkoxyalkyl group; a phenylalkyl group; an alkoxyalkoxy group; ahydroxyalkoxy group; an alkenyl group; an alkynyl group; a cycloalkylgroup; a cycloalkylidenemethyl group; a cycloalkenyl group; acycloalkyloxy group; a phenyloxy group; a phenylalkoxy group; a cyanogroup; a nitro group; an amino group; a mono- or di-alkylamino group; analkanoylamino group; a carboxyl group; an alkoxycarbonyl group; acarbamoyl group; a mono- or di-alkylcarbamoyl group; an alkanoyl group;an alkylsulfonylamino group; a phenylsulfonylamino group; analkylsulfinyl group; an alkylsulfonyl group; a phenylsulfonyl group; aphenyl group optionally substituted by a halogen atom, a cyano group, analkyl group, a haloalkyl group, an alkoxy group, a haloalkoxy group, analkylenedioxy group, an alkyleneoxy group, a mono- or di-alkylaminogroup, a carbamoyl group, or a mono- or di-alkylcarbamoyl group; or aheterocyclyl group optionally substituted by a halogen atom, a cyanogroup, an alkyl group, a haloalkyl group, an alkoxy group, a haloalkoxygroup, a carbamoyl group, or a mono- or di-alkylcarbamoyl group, orR^(4a) and R^(5a) are bonded to each other at the terminals thereof toform an alkylene group; andR^(4b), R^(5b), R^(4c) and R^(5c) are each independently a hydrogenatom; a halogen atom; a hydroxy group; an alkoxy group; an alkyl group;a haloalkyl group; a haloalkoxy group; a hydroxyalkyl group; analkoxyalkyl group; a phenylalkyl group; an alkoxyalkoxy group; ahydroxyalkoxy group; an alkenyl group; an alkynyl group; a cycloalkylgroup; a cycloalkylidenemethyl group; a cycloalkenyl group; acycloalkyloxy group; a phenyloxy group; a phenylalkoxy group; a cyanogroup; a nitro group; an amino group; a mono- or di-alkylamino group; analkanoylamino group; a carboxyl group; an alkoxycarbonyl group; acarbamoyl group; a mono- or di-alkylcarbamoyl group; an alkanoyl group;an alkylsulfonylamino group; a phenylsulfonylamino group; analkylsulfinyl group; an alkylsulfonyl group; a phenylsulfonyl group; aphenyl group optionally substituted by a halogen atom, a cyano group, analkyl group, a haloalkyl group, an alkoxy group, a haloalkoxy group, amethylenedioxy group, an ethyleneoxy group, or a mono- or di-alkylaminogroup; or a heterocyclyl group optionally substituted by a halogen atom,a cyano group, an alkyl group, a haloalkyl group, an alkoxy group or ahaloalkoxy group.

More preferred is a compound wherein R^(1a), R^(2a), R^(3a), R^(1b),R^(2b), and R^(3b) are each independently a hydrogen atom, a halogenatom, a lower alkyl group, a halo-lower alkyl group, a lower alkoxygroup, or a phenyl group;

R^(4a) and R^(5a) are each independently a hydrogen atom; a halogenatom; a lower alkyl group; a halo-lower alkyl group; a phenyl-loweralkyl group; a phenyl group optionally substituted by a halogen atom, acyano group, a lower alkyl group, a halo-lower alkyl group, a loweralkoxy group, a halo-lower alkoxy group, a methylenedioxy group, anethyleneoxy group, a mono- or di-lower alkylamino group, a carbamoylgroup, or a mono- or di-lower alkylcarbamoyl group; or a heterocyclylgroup optionally substituted by a halogen atom, a cyano group, a loweralkyl group, a lower alkoxy group, a carbamoyl group, or a mono- ordi-lower alkylcarbamoyl group, or R^(4a) and R^(5a) are bonded to eachother at the terminals thereof to form a lower alkylene group; andR^(4b), R^(5b), R^(4c) and R^(5c) are each independently a hydrogenatom, a halogen atom, a lower alkyl group, a halo-lower alkyl group, alower alkoxy group, or a halo-lower alkoxy group.

Further preferred is a compound in which Ring B is

wherein R^(4a) is a phenyl group optionally substituted by a halogenatom, a cyano group, a lower alkyl group, a halo-lower alkyl group, alower alkoxy group, a halo-lower alkoxy group, a methylenedioxy group,an ethyleneoxy group, a mono- or di-lower alkylamino group, a carbamoylgroup, or a mono- or di-lower alkylcarbamoyl group; or a heterocyclylgroup optionally substituted by a halogen atom, a cyano group, a loweralkyl group, a lower alkoxy group, a carbamoyl group, or a mono- ordi-lower alkylcarbamoyl group, andR^(5a) is a hydrogen atom, orR^(4a) and R^(5a) are bonded to each other at the terminals thereof toform a lower alkylene group.

Further more preferred is a compound in which Ring A is

wherein R^(1a) is a halogen atom, a lower alkyl group, or a lower alkoxygroup, and R^(2a) and R^(3a) are hydrogen atoms; and Ring B is

wherein R^(4a) is a phenyl group optionally substituted by a substituentselected from the group consisting of a halogen atom, a cyano group, alower alkyl group, a halo-lower alkyl group, a lower alkoxy group, ahalo-lower alkoxy group, a mono- or di-lower alkylamino group, acarbamoyl group, and a mono- or di-lower alkylcarbamoyl group; or aheterocyclyl group optionally substituted by a halogen atom, a cyanogroup, a lower alkyl group, a lower alkoxy group, a carbamoyl group, ora mono- or di-lower alkylcarbamoyl group, and R^(5a) is a hydrogen atom,and Y is —CH₂—.

In more preferable embodiment, R^(4a) is a phenyl group optionallysubstituted by a halogen atom, a cyano group, a lower alkyl group, ahalo-lower alkyl group, a lower alkoxy group, or a halo-lower alkoxygroup; or a heterocyclyl group optionally substituted by a halogen atom,a cyano group, a lower alkyl group, or a lower alkoxy group.

In another preferable embodiment of the present invention, a preferablecompound can be represented by the following formula IA:

wherein R^(A) is a halogen atom, a lower alkyl group or a lower alkoxygroup; R^(B) is a phenyl group optionally substituted by 1-3substituents selected from a halogen atom, a cyano group, a lower alkylgroup, a halo-lower alkyl group, a lower alkoxy group, a halo-loweralkoxy group, a methylenedioxy group, an ethyleneoxy group, a mono- ordi-lower alkylamino group, a carbamoyl group, and a mono- or di-loweralkylcarbamoyl group; or a heterocyclyl group optionally substituted by1-3 substituents selected from a halogen atom, a cyano group, a loweralkyl group, a halo-lower alkyl group, a lower alkoxy group, ahalo-lower alkoxy group, a mono- or di-lower alkylamino group, acarbamoyl group, and a mono- or di-lower alkylcarbamoyl group; and R^(C)is hydrogen atom; or R^(B) and R^(C) taken together are a fused benzenering which may be substituted by a halogen atom, a lower alkyl group, ahalo-lower alkyl group, a lower alkoxy group or a halo-lower alkoxygroup.

In a preferable embodiment, R^(A) is a halogen atom or a lower alkylgroup, R^(C) is hydrogen atom, and R^(B) is phenyl group substituted by1-3 substituents selected from a halogen atom, a cyano group, a loweralkyl group, a halo-lower alkyl group, a lower alkoxy group, ahalo-lower alkoxy group, a methylenedioxy group, an ethyleneoxy group, amono- or di-lower alkylamino group, a carbamoyl group, and a mono- ordi-lower alkylcarbamoyl group; or a heterocyclyl group substituted by1-3 substituents selected from the group consisting of a halogen atom, acyano group, a lower alkyl group, a halo-lower alkyl group, a loweralkoxy group, a halo-lower alkoxy group, a mono- or di-lower alkylaminogroup, a carbamoyl group, and a mono- or di-lower alkylcarbamoyl group.The chemical structure of such compounds are represented by thefollowing formula (IA′):

wherein R^(A) is a halogen atom, or a lower alkyl group, Ring C is aphenyl group substituted by 1-3 substituents selected from the groupconsisting of a halogen atom, a cyano group, a lower alkyl group, ahalo-lower alkyl group, a lower alkoxy group, a halo-lower alkoxy group,a methylenedioxy group, an ethyleneoxy group, a mono- or di-loweralkylamino group, a carbamoyl group, and a mono- or di-loweralkylcarbamoyl group; or a heterocyclyl group substituted by 1-3substituents selected from the group consisting of a halogen atom, acyano group, a lower alkyl group, a halo-lower alkyl group, a loweralkoxy group, a halo-lower alkoxy group, a mono- or di-lower alkylaminogroup, a carbamoyl group, and a mono- or di-lower alkylcarbamoyl group.

In a more preferable embodiment, Ring C is a phenyl group substituted by1-3 substituents selected from the group consisting of a halogen atom, acyano group, a lower alkyl group, a halo-lower alkyl group, a loweralkoxy group, a halo-lower alkoxy group, and a mono- or di-loweralkylamino group; or a heterocyclyl group substituted by a substituentselected from the group consisting of a halogen atom, a cyano group, alower alkyl group, a halo-lower alkyl group, a lower alkoxy group, and ahalo-lower alkoxy group.

Among them, a compound in which Ring C is a phenyl group substituted bya halogen atom, a cyano group, a lower alkyl group, a halo-lower alkylgroup, a lower alkoxy group or a halo-lower alkoxy group; or aheterocyclyl group substituted by a halogen atom, a cyano group, a loweralkyl group, or a lower alkoxy group is preferred.

A preferred heterocyclyl group includes a 5- or 6-membered heterocyclylgroup containing 1 or 2 hetero atoms independently selected from thegroup consisting of a nitrogen atom, an oxygen atom, and a sulfur atom,or a 9- or 10-membered heterocyclyl group containing 1 to 4 hetero atomsindependently selected from the group consisting of a nitrogen atom, anoxygen atom, and a sulfur atom. Specifically, a thienyl group, a pyridylgroup, a pyrimidyl group, a pyrazinyl group, pyrazolyl group, athiazolyl group, a quinolyl group, a tetrazolyl group and an oxazolylgroup are preferred.

In a further preferable embodiment, Ring C is a phenyl group substitutedby a halogen atom or a cyano group, or a pyridyl group substituted by ahalogen atom.

In another preferable embodiment of the present invention, preferred isa compound in which Ring A is

wherein R^(1a) is a halogen atom, a lower alkyl group, or a lower alkoxygroup, and R^(2a) and R^(3a) are hydrogen atoms; and Ring B is

wherein R^(4b) and R^(5b) are each independently a hydrogen atom, ahalogen atom, a lower alkyl group, a halo-lower alkyl group, a loweralkoxy group, or a halo-lower alkoxy group.

In another aspect of the present invention, preferable examples of thecompound I include a compound represented by the following formula IB:

wherein R⁸, R⁹ and R¹⁰ are each independently a hydrogen atom, a halogenatom, a hydroxy group, an alkoxy group, an alkyl group, a haloalkylgroup, a haloalkoxy group, a hydroxyalkyl group, an alkoxyalkyl group,an alkoxyalkoxy group, an alkenyl group, an alkynyl group, a cycloalkylgroup, a cycloalkylidenemethyl group, a cycloalkenyl group, acycloalkyloxy group, an aryloxy group, an arylalkoxy group, a cyanogroup, a nitro group, an amino group, a mono- or di-alkylamino group, analkylcarbonylamino group, a carboxyl group, an alkoxycarbonyl group, acarbamoyl group, a mono- or di-alkylcarbamoyl group, an alkanoyl group,an alkylsulfonylamino group, an arylsulfonylamino group, analkylsulfinyl group, an alkylsulfonyl group, or an arylsulfonyl group;and a group represented by:

wherein R^(6a) and R^(7a) are each independently a hydrogen atom, ahalogen atom, a hydroxy group, an alkoxy group, an alkyl group, ahaloalkyl group, a haloalkoxy group, a hydroxyalkyl group, analkoxyalkyl group, an alkoxyalkoxy group, an alkenyl group, an alkynylgroup, a cycloalkyl group, a cycloalkylidenemethyl group, a cycloalkenylgroup, a cycloalkyloxy group, an aryloxy group, an arylalkoxy group, acyano group, a nitro group, an amino group, a mono- or di-alkylaminogroup, an alkylcarbonylamino group, a carboxyl group, an alkoxycarbonylgroup, a carbamoyl group, a mono- or di-alkylcarbamoyl group, analkanoyl group, an alkylsulfonylamino group, an arylsulfonylamino group,an alkylsulfinyl group, an alkylsulfonyl group, or an arylsulfonyl groupand R^(6b) and R^(7b) are each independently a hydrogen atom, a halogenatom, an alkyl group, a haloalkyl group, or an alkoxy group.

Among the compounds represented by the formula IB, more preferred is acompound in which R⁸, R⁹ and R¹⁰ are each independently a hydrogen atom,a halogen atom, a lower alkyl group, a cycloalkyl group, a hydroxy-loweralkyl group, a halo-lower alkyl group, a lower alkoxy-lower alkyl group,a lower alkoxy group, a cycloalkoxy group, a halo-lower alkoxy group, ora lower alkoxy-lower alkoxy group, and a group represented by:

wherein R^(6a), R^(7a) are each independently a hydrogen atom, a halogenatom, a lower alkyl group, a cycloalkyl group, a hydroxy-lower alkylgroup, a halo-lower alkyl group, a lower alkoxy-lower alkyl group, alower alkoxy group, a cycloalkoxy group, a halo-lower alkoxy group, or alower alkoxy-lower alkoxy group, or a group represented by:

wherein R^(6b) and R^(7b) are each independently a hydrogen atom, ahalogen atom, a lower alkyl group, a halo-lower alkyl group, or a loweralkoxy group.

In another aspect of the present invention, preferable examples of thecompound I include a compound represented by the following formula IC:

wherein Ring B′ is an optionally substituted benzene ring, an optionallysubstituted unsaturated monocyclic heterocyclic ring, or an optionallysubstituted unsaturated fused heterobicyclic ring.

Preferable examples of Ring B′ include a benzene ring and a heterocyclicring, both of which may have a substituent(s) selected from the groupconsisting of a halogen atom; a cyano group; a lower alkyl groupoptionally substituted by a halogen atom; a lower alkoxy groupoptionally substituted by a halogen atom; a lower alkanoyl group; amono- or di-lower alkylamino group; a lower alkoxycarbonyl group; acarbamoyl group; a mono- or di-lower alkylcarbamoyl group; a phenylgroup optionally substituted by a substituent(s) selected from a halogenatom, a cyano group, a lower alkyl group optionally substituted by ahalogen atom, a lower alkoxy group optionally substituted by a halogenatom, a lower alkanoyl group, a mono- or di-lower alkylamino group, alower alkoxycarbonyl group, a carbamoyl group, or a mono- or di-loweralkylcarbamoyl group; a heterocyclyl group optionally substituted by asubstituent(s) selected from a halogen atom, a cyano group, a loweralkyl group optionally substituted by a halogen atom, a lower alkoxygroup optionally substituted by a halogen atom, a lower alkanoyl group,a mono- or di-lower alkylamino group, a lower alkoxycarbonyl group, acarbamoyl group, or a mono- or di-lower alkylcarbamoyl group; analkylene group; and an oxo group.

More preferable examples of Ring B′ include a benzene ring which may besubstituted by a substituent selected from the group consisting of ahalogen atom; a cyano group; a lower alkyl group optionally substitutedby a halogen atom; a lower alkoxy group optionally substituted by ahalogen atom; a mono- or di-lower alkylamino group; a phenyl groupoptionally substituted by a halogen atom, a cyano group, a lower alkylgroup optionally substituted by a halogen atom, a lower alkoxy groupoptionally substituted by a halogen atom; a heterocyclyl groupoptionally substituted by a halogen atom, a cyano group, a lower alkylgroup optionally substituted by a halogen atom, a lower alkoxy groupoptionally substituted by a halogen atom.

Preferred compound of the present invention may be selected from thefollowing group:

-   1-(β-D-glucopyranosyl)-4-chloro-3-(6-ethylbenzo[b]thiophen-2-ylmethyl)benzene;-   1-(β-D-glucopyranosyl)-4-chloro-3-[5-(5-thiazolyl)-2-thienylmethyl]benzene;-   1-(β-D-glucopyranosyl)-4-chloro-3-(5-phenyl-2-thienylmethyl)benzene;-   1-(β-D-glucopyranosyl)-4-methyl-3-[5-(4-fluorophenyl)-2-thienylmethyl]benzene;-   1-(β-D-glucopyranosyl)-4-chloro-3-[5-(2-pyrimidinyl)-2-thienylmethyl]benzene;-   1-(β-D-glucopyranosyl)-4-methyl-3-[5-(2-pyrimidinyl)-2-thienylmethyl]benzene;-   1-(β-D-glucopyranosyl)-4-chloro-3-[5-(3-cyanophenyl)-2-thienylmethyl]benzene;-   1-(β-D-glucopyranosyl)-4-chloro-3-[5-(4-cyanophenyl)-2-thienylmethyl]benzene;-   1-(β-D-glucopyranosyl)-4-methyl-3-[5-(6-fluoro-2-pyridyl)-2-thienylmethyl]benzene;-   1-(β-D-glucopyranosyl)-4-chloro-3-[5-(6-fluoro-2-pyridyl)-2-thienylmethyl]benzene;-   1-(β-D-glucopyranosyl)-4-methyl-3-[5-(3-difluoromethyl-phenyl)-2-thienylmethyl]benzene;-   1-(β-D-glucopyranosyl)-4-methyl-3-[5-(3-cyanophenyl)-2-thienylmethyl]benzene;-   1-(β-D-glucopyranosyl)-4-methyl-3-[5-(4-cyanophenyl)-2-thienylmethyl]benzene;-   1-(β-D-glucopyranosyl)-4-chloro-3-[5-(6-fluoro-3-pyridyl)-2-thienylmethyl]benzene;-   1-(β-D-glucopyranosyl)-4-fluoro-3-(5-(3-cyanophenyl)-2-thienylmethyl)benzene;    the pharmaceutically acceptable salt thereof; and    the prodrug thereof.

Particularly Preferred compounds of the present invention include:

-   1-(β-D-glucopyranosyl)-4-methyl-3-[5-(3-cyano-phenyl)-2-thienylmethyl]benzene,    or a pharmaceutically acceptable salt thereof, or a prodrug thereof;-   1-(β-D-glucopyranosyl)-4-methyl-3-[5-(4-cyano-phenyl)-2-thienylmethyl]benzene,    or a pharmaceutically acceptable salt thereof, or a prodrug thereof;-   1-(β-D-glucopyranosyl)-4-methyl-3-[5-(4-fluoro-phenyl)-2-thienylmethyl]benzene,    or a pharmaceutically acceptable salt thereof, or a prodrug thereof;-   1-(β-D-glucopyranosyl)-4-chloro-3-[5-(3-cyano-phenyl)-2-thienylmethyl]benzene,    or a pharmaceutically acceptable salt thereof, or a prodrug thereof;-   1-(β-D-glucopyranosyl)-4-methyl-3-[5-(6-fluoro-2-pyridyl)-2-thienylmethyl]benzene,    or a pharmaceutically acceptable salt thereof, or a prodrug thereof;-   1-(β-D-glucopyranosyl)-4-chloro-3-[5-(6-fluoro-2-pyridyl)-2-thienylmethyl]benzene,    or a pharmaceutically acceptable salt thereof, or a prodrug thereof;-   1-(β-D-glucopyranosyl)-4-chloro-3-[5-(6-fluoro-3-pyridyl)-2-thienylmethyl]benzene,    or a pharmaceutically acceptable salt thereof, or a prodrug thereof;    and-   1-(β-D-glucopyranosyl)-4-fluoro-3-(5-(3-cyanophenyl)-2-thienylmethyl)benzene,    or a pharmaceutically acceptable salt thereof, or a prodrug thereof.

The compound (I) of the present invention exhibits an excellentinhibitory activity against sodium-dependent glucose transporter, and anexcellent blood glucose lowering effect. Therefore, the compound of thepresent invention is useful for treating or delaying the progression oronset of diabetes mellitus, diabetic retinopathy, diabetic neuropathy,diabetic nephropathy, delayed wound healing, insulin resistance,hyperglycemia, hyperinsulinemia, elevated blood levels of fatty acids,elevated blood levels of glycerol, hyperlipidemia, obesity,hypertriglyceridemia, Syndrome X, diabetic complications,atherosclerosis, or hypertension. In particular, the compound of thepresent invention is useful in the treatment or the prophylaxis ofdiabetes mellitus (type 1 and type 2 diabetes mellitus, etc.), diabeticcomplications (such as diabetic retinopathy, diabetic neuropathy,diabetic nephropathy) or obesity, or is useful in the treatment ofpostprandial hyperglycemia.

The compound (I) of the present invention or a pharmaceuticallyacceptable salt thereof may be administered either orally orparenterally, and can be used in the form of a suitable pharmaceuticalpreparation. Suitable pharmaceutical preparation for oral administrationincludes, for example, solid preparation such as tablets, granules,capsules, powders, etc., or solution preparations, suspensionpreparations, or emulsion preparations, etc. Suitable pharmaceuticalpreparation for parenteral administration includes, for example,suppositories; injection preparations and intravenous drip preparationsusing distilled water for injection, physiological saline solution oraqueous glucose solution; or inhalant preparations.

The dosage of the present compound (I) or a pharmaceutically acceptablesalt thereof may vary according to the administration routes, ages, bodyweight, conditions of a patient, or kinds and severity of a disease tobe treated, and it is usually in the range of about 0.1 to 50 mg/kg/day,preferably in the range of about 0.1 to 30 mg/kg/day.

The compound of the formula I may be used, if necessary, in combinationwith one or more of other antidiabetic agents, one or more agents fortreating diabetic complications, and/or one or more agents for treatmentof other diseases. The present compound and these other agents may beadministered in the same dosage form, or in a separate oral dosage formor by injection.

The other antidiabetic agents include, for example, antidiabetic orantihyperglycemic agents including insulin, insulin secretagogues, orinsulin sensitizers, or other antidiabetic agents having an actionmechanism different from SGLT inhibition, and 1, 2, 3 or 4 of theseother antidiabetic agents may preferably be used. Concrete examplesthereof are biguanide compounds, sulfonylurea compounds, α-glucosidaseinhibitors, PPARγ agonists (e.g., thiazolidinedione compounds), PPARα/γdual agonists, dipeptidyl peptidase IV (DPP4) inhibitors, mitiglinidecompounds, and/or nateglinide compounds, and insulin, glucagon-likepeptide-1 (GLP-1), PTP1B inhibitors, glycogen phosphorylase inhibitors,RXR modulators, and/or glucose 6-phosphatase inhibitors.

The agents for treatment of other diseases include, for example, ananti-obesity agent, an antihypertensive agent, an antiplatelet agent, ananti-atherosclerotic agent and/or a hypolipidemic agent.

The SGLT inhibitors of the formula I may be used in combination withagents for treatment of diabetic complications, if necessary. Theseagents include, for example, PKC inhibitors and/or ACE inhibitors.

The dosage of those agents may vary according to ages, body weight, andconditions of patients, and administration routes, dosage forms, etc.

These pharmaceutical compositions may be orally administered tomammalian species including human beings, apes, dogs, etc., for example,in the dosage form of tablet, capsule, granule or powder, orparenterally administered in the form of injection preparation, orintranasally, or in the form of transdermal patch.

The present compound of the formula I may be prepared by the followingProcesses.

Process 1

The compound of the formula I may be prepared by a method as shown inthe following scheme:

wherein R^(11a) is a hydrogen atom or a protecting group for a hydroxygroup, and R^(11b), R^(11c) and R^(11d) are each independently aprotecting group for a hydroxy group, and other symbols are as definedabove.

The compound of the formula I may be prepared by deprotecting thecompound of the formula II.

In the compound of the formula II, the protecting group for hydroxygroup may be any conventional protecting groups, and a benzyl group, anacetyl group, and an alkylsily group such as a trimethylsilyl group maybe used. Further, the protecting group for hydroxy group may form acetalor silylacetal together with adjacent hydroxy groups. Examples of suchprotecting group include an alkylidene group such as an isopropylidenegroup, a sec-butylidene group, etc., a benzylidene group, or adialkylsilylene group such as di-tert-butylsilylene group, etc., whichcan be formed, for example, by combining R^(11c) and R^(11d) at theterminal thereof.

The deprotection can be carried out according to the kinds of protectinggroup to be removed, for example, by conventional processes such asreduction, hydrolysis, acid treatment, fluoride treatment, etc.

For example, when a benzyl group is to be removed, the deprotection canbe carried out by (1) catalytic reduction using a palladium catalyst(e.g., palladium-carbon, palladium hydroxide) under hydrogen atmospherein a suitable solvent (e.g., methanol, ethanol, ethyl acetate); (2)treatment with an dealkylating agent such as boron tribromide, borontrichloride, boron trichloride.dimethylsulfide complex, oriodotrimethylsilane in a suitable solvent (e.g., dichloromethane); or(3) treatment with a lower alkylthiol such as ethanethiol in thepresence of a Lewis acid (e.g., boron trifluoride.diethyl ether complex)in a suitable solvent (e.g., dichloromethane).

When a protecting group is removed by hydrolysis, the hydrolysis can becarried out by treating the compound of formula II with a base (e.g.,sodium hydroxide, potassium hydroxide, lithium hydroxide, sodiummethoxide, sodium ethoxide, etc.) in a suitable solvent (e.g.,tetrahydrofuran, dioxane, methanol, ethanol, water, etc.).

Acid treatment can be carried out by treating the compound of formula IIwith an acid (e.g., hydrochloric acid, p-toluenesulfonic acid,methanesulfonic acid, trifluoroacetic acid, etc.) in a suitable solvent(e.g., methanol, ethanol, etc.).

In case of the fluoride treatment, it can be carried out by treating thecompound of formula II with a fluoride (e.g., hydrogen fluoride,hydrogen fluoride-pyridine, tetrabutylammonium fluoride, etc.) in asuitable solvent (e.g., acetic acid, a lower alcohol (methanol, ethanol,etc.), acetonitrile, tetrahydrofuran, etc.).

The deprotection reaction can be preferably carried out under cooling orwith heating, for example, at a temperature of from 0° C. to 50° C.,more preferably at a temperature of from 0° C. to room temperature.

Accordingly, a compound of formula (IA′):

wherein the symbols are the same as defined above, can be prepared bydeprotecting a compound of formula (II-A):

wherein the symbols are the same as defined above, as described above.Process 2

The compound of the formula I wherein X is a carbon atom may be preparedby a method as shown in the following scheme:

wherein R¹² is a lower alkyl group, and other symbols are as definedabove.

The compound of the formula I-a may be prepared by reducing the compoundof the formula III.

The reduction can be carried out by treatment with a silane reagent, inthe presence of an acid, in a suitable solvent or in the absence of asolvent.

As the acid, for example, a Lewis acid such as boron trifluoride.diethylether complex, titanium tetrachloride, etc., and a strong organic acidsuch as trifluoroacetic acid, methanesulfonic acid, etc., may preferablybe used.

As the silane reagent, for example, a trialkylsilane such astriethylsilane, triisopropylsilane, etc. may preferably be used.

As the solvent, any kinds of solvent may be used as long as it does notaffect the reaction, and for example, acetonitrile, dichloromethane, oran acetonitrile/dichloromethane mixture may preferably be used.

Accordingly, the compound of the formula (IA′):

wherein the symbols are the same as defined above, can be prepared byreducing a compound of formula (III-A):

wherein the symbols are the same as defined above, as described above.Process 3

The compound of the formula I wherein X is a carbon atom may be preparedby a method as shown in the following scheme:

wherein the symbols are as defined above.

Namely, the compound of the formula I-b may be prepared by reducing thecompound of the formula IV.

The reduction can be carried out in a manner similar to Process 2. Inother words, it can be carried out by treatment with a silane reagent(e.g., triethylsilane, etc.), in the presence of a Lewis acid (e.g.,boron trifluoride diethyl ether complex, etc.), in a suitable solvent(e.g., acetonitrile, dichloromethane, etc.).

The compound of the present invention thus obtained may be isolated andpurified by a conventional method well known in the organic syntheticchemistry such as recrystallization, column chromatography, etc.

The starting compound represented by the formula (II), (III) or (IV) maybe prepared by either one of the following steps (a)-(l).

Steps (a) and (b):

In the above scheme, R¹³ is (1) a bromine atom or an iodine atom when Xis a carbon atom; or (2) a hydrogen atom when X is a nitrogen atom,R^(11e) is a protecting group for hydroxy group, and the other symbolsare as defined above.Step (a):

Among the compounds of the formula II, the compound wherein X is acarbon atom may be prepared by coupling the compound of the formula VIIwith the compound of the formula VI to give the compound of formula V,followed by reduction of the compound of the formula V.

The coupling reaction can be carried out by lithiating the compound ofthe formula VII, followed by reacting the resultant with the compound ofthe formula VI.

In particular, the compound of the formula VII can be treated with analkyllithium, followed by reacting the resultant with the compound ofthe formula VI. As the alkyllithium, methyl lithium, n-butyl lithium,t-butyl lithium, etc. are preferably used. The solvent may be anysolvent which does not disturb the reaction, and ethers such astetrahydrofuran, diethyl ether, etc., are preferably used. This reactioncan be carried out from under cooling (e.g., at −78° C.) to roomtemperature.

The reduction can be carried out in a manner similar to Process 2.Namely, it can be carried out by treating the compound of formula V witha silane reagent (e.g., triethylsilane, etc.) in the presence of a Lewisacid (e.g., boron trifluoride.diethyl ether complex, etc.) in a suitablesolvent (e.g., acetonitrile, dichloromethane, etc.).

Step (b)

Among the compounds of the formula II, the compound wherein X is anitrogen atom may be prepared by silylating the compound of the formulaVII in a solvent, followed by reacting the resultant with the compoundof the formula VIII (e.g., an α- or β-D-glucose pentaacetate, etc.) inthe presence of a Lewis acid.

The silylation reaction can be carried out by treating the compound offormula VII with a silylating agent in a solvent. The silylating agentincludes, for example, N,O-bis(trimethylsilyl)acetamide,1,1,1,3,3,3-hexamethyl-disilazane, etc.

The solvent may be, for example, halogenated hydro-carbons such asdichloromethane, dichloroethane, chloroform, etc., ethers such asdiethyl ether, tetrahydrofuran, 1,2-dimethoxyethane, etc., acetonitrile,etc.

This reaction is preferably carried out under cooling or with heating,for example, at a temperature of from 0° C. to 60° C., preferably at atemperature of from room temperature to 60° C.

The reaction with the compound of the formula VIII can be carried out ina solvent in the presence of a Lewis acid.

The Lewis acid includes, for example, trimethylsilyltrifluoromethanesulfonate, titanium tetrachloride, tin tetrachloride,boron trifluoride.diethyl ether complex.

The solvent may be, for example, halogenated hydro-carbons such asdichloromethane, dichloroethane, chloroform, etc., acetonitrile, etc.

This reaction can be carried out under cooling or with heating, forexample, at a temperature of from 0° C. to 100° C., preferably at atemperature of from room temperature to 60° C.

Step (c):

Among the compounds of the formula II, the compound wherein X is acarbon atom and R^(11a) is a hydrogen atom may be prepared by a methodas shown in the following scheme:

wherein R^(13a) is a bromine atom or an iodine atom, and the othersymbols are as defined above.

Namely, the compounds of the formula II-a may be prepared by couplingthe compound of the formula VII-a with the compound of the formula X oran ester thereof to give the compound of the formula IX, followed byhydrating the compound of the formula IX.

The ester of the compound of the formula X includes, for example, alower alkyl ester thereof, and a compound represented by the formula XI:

wherein R¹⁴ is a lower alkyl group, m is 0 or 1, and the other symbolsare as defined above.

The coupling reaction of the compound of the formula VII-a with thecompound of the formula X or an ester thereof can be carried out in thepresence of a base and a palladium catalyst in a suitable solvent.

The base includes an inorganic base such as an alkali metal carbonate(e.g., sodium carbonate, potassium carbonate, etc.), an alkali metalhydrogen carbonate (e.g., sodium hydrogen carbonate, potassium hydrogencarbonate, etc.), an alkali metal hydroxide (e.g., sodium hydroxide,potassium hydroxide, etc.), potassium fluoride, potassium phosphate,etc., and an organic base such as a tri-lower alkylamine (e.g.,triethylamine, diisopropylethylamine, etc.), a cyclic tertiary amine(e.g., 1,4-diazabicyclo[2.2.2]octane, 1,5-diazabicyclo[4.3.0]nona-5-ene,1,8-diazabicyclo[5.4.0]undeca-7-ene, etc.).

The palladium catalyst may be a conventional catalyst such astetrakis(triphenyl)phosphinepalladium(0), palladium(II)acetate,palladium(II) chloride, bis(triphenyl)phosphine palladium(II) chloride,palladium(II) chloride.1,1-bis(diphenylphosphino)ferrocene complex, etc.

The solvent may be any inert solvent which does not disturb thereaction, for example, ethers such as tetrahydrofuran, dioxane,1,2-dimethoxyethane, etc., amide solvents such as N,N-dimethylformamide,1,3-dimethyl-2-imidazolidinone, etc., aromatic hydrocarbons such astoluene, xylene, etc., dimethylsulfoxide, water, and if desired, amixture of two or more of these solvents.

This reaction is preferably carried out with heating, for example, at atemperature of from 50° C. to a boiling point of the reaction mixture,and more preferably at a temperature of from 50° C. to 100° C.

The hydration reaction of the compound of the formula IX can be carriedout, for example, by hydroboration, more specifically, by reacting withdiborane, borane tetrahydrofuran complex, or 9-borabicyclononane, etc.in a suitable solvent, followed by treating with hydrogen peroxidesolution in the presence of a base (e.g., an alkali metal hydroxide suchas sodium hydroxide, etc.), or by treating with an oxidizing reagentsuch as sodium perborate, and oxodiperoxymolybdenum (pyridine)(hexamethylphosphoric triamide) in a suitable solvent.

The solvent may be any inert solvent which does not disturb thereaction, for example, ethers such as diethyl ether, diisopropyl ether,tetrahydrofuran, dioxane, 1,2-dimethoxyethane, etc., aromatichydrocarbons such as benzene, toluene, xylene, etc., water, and ifdesired, a mixture of two or more of these solvents. This reaction canbe carried out at a temperature of a broad range such as under coolingor with heating, and preferably carried out at a temperature of from−10° C. to a boiling point of the reaction mixture.

Step (d):

Among the compound of the formula II, the compound wherein Ring A is abenzene ring may be prepared in a method as shown in the followingscheme:

wherein the symbols are as defined above.

Namely, the compounds of the formula II-b may be prepared by couplingthe compound of the formula XIV with the compound of the formula XIII,to give the compound of the formula XII, followed by reduction of thecompound of the formula XII.

The coupling reaction can be carried out in a manner similar to Step(a). Namely, it can be carried out by lithiating the compound of formulaXIV with an alkyl lithium (e.g., n-butyl lithium, tert-butyl lithium,etc.) in a suitable solvent (e.g., diethyl ether, tetrahydrofuran,etc.), followed by reacting the resultant with the compound (XIII).

The reduction reaction can be carried out by (1) treatment with a silanereagent (e.g., trialkyl silane such as triethyl silane, etc.) in asuitable solvent (e.g., acetonitrile, dichloromethane, etc.), at −30° C.to 60° C., in the presence of a Lewis acid such as boron trifluoridediethyl ether complex or trifluoroacetic acid, (2) treatment withiodotrimethylsilane, or (3) treatment with a reducing agent (e.g.,borohydrides such as sodium boron hydride, sodium triacetoxyborohydride,etc., aluminum hydrides such as lithium aluminum hydride, etc.) in thepresence of an acid (e.g., a strong acid such as trifluoroacetic acid,etc., and a Lewis acid such as aluminum chloride, etc.).

Step (e):

The compound of the formula III may be prepared by a method as shown inthe following scheme:

wherein the symbols are as defined above.

Namely, the compound of the formula III may be prepared by deprotectingthe compound of the formula V which is a synthetic intermediate of Step(a), followed by treating the resultant compound with an acid in analcohol solvent.

The deprotection reaction can be carried out in a manner similar toProcess 1. Namely, it can be carried out by subjecting the compound V toan acid treatment, reduction, or a fluoride treatment, etc.

Following the deprotection reaction, the resultant compound is treatedwith an acid in a suitable alcohol. The acid includes, for example, aninorganic acid such as hydrochloric acid, nitric acid, sulfuric acid,etc., an organic acid such as p-toluenesulfonic acid, methanesulfonicacid, trifluoroacetic acid, etc. The alcohol includes a conventionalalkyl alcohol which does not disturb the reaction, for example,methanol, ethanol, n-propanol, i-propanol, n-butanol, etc.

Additionally, the deprotection reaction and acid treatment may becarried out in the same step, depending on the kind of the protectinggroup.

Step (f):

The compound of the formula IV may be prepared by a method as shown inthe following scheme:

wherein the symbols are as defined as above.

First, the compound of the formula XVI is coupled with the compound ofthe formula VI to give the compound of the formula XV. Then, afterprotecting groups are removed from the compound of the formula XV, theresultant is treated with an acid in an alcohol to give the compound ofthe formula IV.

The coupling reaction can be carried out in a manner similar to Step(a). Namely, the compound XVI is treated with an alkyl lithium (e.g.,n-butyl lithium, tert-butyl lithium, etc,) in a suitable solvent (e.g.,diethyl ether, tetrahydrofuran, etc.), followed by reacting theresultant with the compound VI.

The removal of protecting groups and the acid treatment are carried outin a manner similar to Step (e). Namely, it can be carried out bysubjecting the compound XV to reduction, acid treatment or fluoridetreatment, depending on the kind of the protecting group to be removed,followed by treating the resultant with an acid (e.g., hydrochloricacid, p-toluenesulfonic acid, methanesulfonic acid, trifluoroaceticacid, etc.) in a suitable solvent (e.g., methanol, ethanol, etc.).

Step (g):

The compound of the formula II may be prepared by a method as shown inthe following scheme:

wherein R²⁰ is a trialkylstannyl group, or a dihydroxyboryl group or anester thereof, and the other symbols are as defined above. Examples ofesters of dihydroxyboryl group include an ester with a lower alkylalcohol such as methanol and ethanol and an ester with a lower alkylenediol such as pinacol.

Namely, the compound of the formula II may be prepared by coupling thecompound XVII with the compound XVIII in a suitable solvent, in thepresence of a palladium catalyst, and in the presence or in the absenceof a base.

The coupling reaction can be carried out in a manner similar to Step(c).

Step (h):

Among the compound of the formula II, the compound wherein n is 1 and Xis a carbon atom may be prepared in a method as shown in the followingscheme:

wherein the symbols are as defined above.

Namely, the compound of the formula II may be prepared by the followingsteps: (1) treating the compound of the formula XXII with a halogenatingagent in a suitable solvent or in the absence of a solvent, followed bycondensation of the resultant with the compound of the formula XXI inthe presence of a Lewis acid to give the compound of formula XX, (2)reducing the compound of formula XX, and (3) further reducing thecompound of formula XIX.

The halogenating agent includes a conventional halogenating agent suchas thionyl chloride, phosphorus oxychloride, oxalyl chloride, etc.

The solvent may be any solvent which does not disturb the reaction, andfor example, dichloromethane, carbon tetrachloride, tetrahydrofuran,toluene, etc. may be mentioned.

Further, in the present reaction, the reaction suitably proceeds byadding a catalyst such as dimethylformamide, etc.

The condensation reaction of the compound (XXII) and the compound (XXI)can be carried out according to a conventional method as known asFriedel-Crafts reaction, in the presence of a Lewis acid and in asuitable solvent.

The Lewis acid includes aluminum chloride, boron trifluoride.diethylether complex, tin(IV) chloride, titanium tetrachloride, etc. which areconventionally used in Friedel-Crafts reaction.

The solvent includes halogenated hydrocarbons such as dichloromethane,carbon tetrachloride, dichloroethane, etc.

The reduction of the compound of formula XX can be carried out bytreating the compound (XX) with borohydrides (e.g., sodium borohydride,sodium triacetoxyborohydride, etc.) in a suitable solvent (e.g.,tetrahydrofuran, etc.).

The present reaction can be carried out under cooling or with heating,for example, at a temperature of from −30° C. to 60° C.

The subsequent reduction reaction can be carried out by treating thecompound of formula XIX with a silane reagent (e.g., trialkyl silane,etc.) in a suitable solvent (e.g., acetonitrile, dichloromethane, etc.),in the presence of an acid (e.g., a Lewis acid such as borontrifluoride.diethyl ether complex, etc., and a strong organic acid suchas trifluoroacetic acid, methanesulfonic acid, etc.), or by treatingwith a hydrazine in a suitable solvent (e.g., ethylene glycol, etc.) inthe presence of a base (e.g., potassium hydroxide, etc.).

The present reaction can be carried out under cooling or with heating,for example, at a temperature of from −30° C. to 60° C.

Step (i):

Among the compounds of the formula II, the compound wherein X is anitrogen atom may be prepared by a method as shown in the followingscheme:

wherein R²¹ is a leaving group, and the other symbols are as definedabove.

Examples of the leaving group include a halogen atom such as chlorineatom and bromine atom.

Namely, the compound of the formula II-d may be prepared by condensationof the compound of the formula XXIII with the compound of the formulaXXIV.

The condensation reaction can be carried out in a suitable solvent suchas acetonitrile, etc., in the presence of a base (e.g., an alkali metalhydroxide, such as potassium hydroxide, etc.).

Step (j):

Among the compound of the formula II, the compound wherein Ring A is apyrazole substituted by a lower alkyl group, X is a nitrogen atom and Yis —CH₂— may be prepared by a method as shown in the following scheme:

wherein R²² and R²³ are each independently a lower alkyl group, and theother symbols are as defined above.

Namely, the compound II-e may be prepared by condensation of thecompound of the formula XXV with the compound of the formula XXVI in asuitable solvent (e.g., ethers such as tetrahydrofuran, etc., anaromatic hydrocarbons such as toluene, etc.).

Step (k):

Among the compounds represented by formula (II), a compound wherein Y is—CH₂— group can be prepared by a method as shown in the followingscheme:

wherein the symbols are the same as defined above.

The compound (II-f) can be prepared by condensing a compound of formula(XL) with a compound of formula (XLI), and reducing a compound offormula (XLII).

The condensation reaction can be carried out in a similar manner asdescribed in Step (h). Namely, the condensation reaction can be carriedout in a suitable solvent (e.g., dichloromethane, carbon tetrachloride,dichloroethane, etc.) in the presence of a Lewis acid (e.g., aluminumchloride, zinc chloride, titanium tetrachloride, etc.).

The reduction reaction can be carried out in a similar manner asdescribed in Step (h).

Step (l)

Among the compounds represented by the formula (II), a compound whereinRing B is an isoindolinyl or dihydroisoquinolinyl group can be preparedby a method as shown in the following scheme:

wherein the symbols are the same as defined above.

A compound of formula (II-g) can be prepared by reductive amination of acompound of formula (XLIII) with isoindoline or dihydroisoquinoline.Reductive amination can be carried out in a suitable solvent (e.g.,tetrahydrofuran, acetic acid, dichloroethane, etc.) in the presence of areducing agent such as borohydrides (e.g., sodium borohydride, sodiumtriacetoxyborohydride) and aluminum hydrides (e.g., lithium aluminumhydride).

Further, the compound of the present invention may be converted to eachother within the objective compounds of the present invention. Suchconversion reaction may be carried out according to a conventionalmethod, depending on the kind of the objective substituents. It may bepreferable that functional groups in the compound would be protectedbefore the conversion. The protective groups for the functional groupscan be selected from conventional ones which can be removed by usualmethods.

For example, a compound having as a substituent of Ring B an aryl groupsuch as phenyl group or a heterocyclyl group may be prepared by couplingthe compound in which substituents of the Ring B is a halogen atom suchas a bromine atom, with a suitable phenylboronic acid, phenyltin,heterocyclylboronic acid, or heterocyclyltin.

The coupling reaction may be carried out in a manner similar to Step (c)or Step (g), or in a method as described in the following Examples.

Accordingly, the compound of formula (IA′):

wherein the symbols are the same as defined above, can be prepared by(1) protecting a compound of formula (I-c):

wherein Z is a halogen atom such as chlorine, bromine and iodine atomand R^(A) is the same as defined above, to afford a compound of formula(II-h):

wherein the symbols are the same as defined above, (2) coupling thecompound (II-h) with a compound of formula (XLIV):

wherein R^(X) is B(OH)₂ or an ester thereof, or Sn(lower alkyl)₃, andRing C is the same as defined above, to afford a compound of formula(II-A):

wherein the symbols are the same as defined above, and (3) removing theprotecting groups. Examples of esters of B(OH)₂ include an ester with alower alkyl alcohol such as methanol and ethanol and an ester with alower alkylene diol such as pinacol. Protection of hydroxyl groups canbe carried out by conventional methods. Coupling reaction anddeprotection can be carried out as described in Step (c) or (g) andProcess 1, respectively.

Additionally, the compound of formula (IA′):

wherein the symbols are the same as defined above, can be prepared by(1) converting Z group of a compound of formula (II-h) to B(OH)₂ or anester thereof, (2) coupling said compound with a compound of formula(XLV):

wherein R^(X1) is a halogen atom such as chlorine, bromine and iodineatom and Ring C is the same as defined above, and (3) removing theprotecting groups.

Examples of esters of B(OH)₂ include an ester with a lower alkyl alcoholsuch as methanol and ethanol and an ester with a lower alkylene diolsuch as pinacol.

Conversion of a halogen atom to B(OH)₂ or an ester thereof can becarried out in a conventional method. For example, conversion of ahalogen atom to B(OH)₂ can be carried out by treating the compound(II-h) with an alkyl lithium such as tert-butyl lithium in a suitablesolvent (e.g., tetrahydrofuran), reacting the resulting compound with atri-alkoxyborane in a suitable solvent (e.g., tetrahydrofuran), andhydrolyzing the resulting compound with an acid (such as acetic acid).And conversion of a halogen atom to an ester of B(OH)₂ can be carriedout by treating the compound (II-h) with an alkyl lithium (such astert-butyl lithium) in a suitable solvent (e.g., tetrahydrofuran),reacting the resulting compound with a tri-alkoxyborane in a suitablesolvent (e.g., tetrahydrofuran), and reacting the resulting compoundwith an appropriate alcohol in a suitable solvent (e.g.,tetrahydrofuran) or without solvent. Coupling reaction and deprotectioncan be carried out as described in Step (c) or (g) and Process 1,respectively.

In the present compound, the compound wherein heteroatom is oxidized(e.g., S-oxide, S,S-oxide, or N-oxide compounds) may be prepared byoxidizing a corresponding S-form or N-form.

The oxidation reaction can be carried out by a conventional method, forexample, by treatment with an oxidizing agent (e.g., peracids such ashydrogen peroxide, m-chloroperbenzoic acid, peracetic acid, etc.) in asuitable solvent (e.g., halogenated hydrocarbons such asdichloromethane, etc.).

The starting compounds of the respective steps described above may beprepared by the methods as disclosed in Reference Examples or a processas mentioned below.

(1) Among the compounds of the formula VII, the compound wherein Y is—CH₂— may be prepared by a method as shown in the following scheme:

wherein R¹⁵ is a hydrogen atom or a halogen atom, and the other symbolsare as defined above.

Namely, the compound of the formula VII-b may be prepared by couplingthe compound of the formula XXVIII with the compound of the formula XXIXto give the compound of the formula XXVII, followed by reducing theobtained compound of the formula XXVII.

The coupling reaction of the present step may be carried out in a mannersimilar to Step (a). Namely, the compound of the formula XXVIII istreated with an alkyl lithium (e.g., n-butyl lithium, tert-butyllithium, etc.) in a suitable solvent (e.g., diethyl ether,tetrahydrofuran, etc.), followed by reacting the resultant with thecompound of the formula XXIX.

The reduction reaction may be carried out in a manner similar to Step(d), more specifically, by (1) treatment with a silane reagent such astriethylsilane, etc., in a suitable solvent (e.g., acetonitrile,dichloromethane, etc.), at −30° C. to 60° C., in the presence of a Lewisacid such as boron trifluoride.diethyl ether complex or trifluoroaceticacid, (2) treatment with iodotrimethylsilane, or (3) treatment with areducing agent (e.g., borohydrides such as sodium boron hydride, sodiumtriacetoxyborohydride, etc., aluminum hydrides such as lithium aluminumhydride, etc.) in the presence of an acid (e.g., a strong acid such astrifluoroacetic acid, etc., a Lewis acid such as aluminum chloride,etc.).

(2) Among the compound of the formula VII, the compound wherein X is acarbon atom and Y is —CH₂— may be prepared by a method as shown in thefollowing scheme:

wherein R¹⁶ is a halogen atom, and the other symbols are as definedabove.

The present process may be carried out in a manner similar to Step (h)as mentioned above.

Namely, the compound of the formula VII-c may be prepared by treatingthe compound of the formula XXXIII with a halogenating reagent (e.g.,thionyl chloride, phosphorus oxychloride, oxalyl chloride, etc.) in asuitable solvent (e.g., dichloromethane, carbon tetrachloride,tetrahydrofuran, toluene, etc.) or in the absence of a solvent, to givethe compound of the formula XXXII, subsequently by condensing thiscompound with the compound of the formula XXXI in a suitable solvent(e.g., dichloromethane, carbon tetrachloride, dichloroethane, etc.) inthe presence of a Lewis acid (e.g., aluminum chloride, zinc chloride,titanium tetrachloride, etc.), to give the compound of the formula XXX,and further by reducing the obtained compound.

The reduction reaction can be carried out by treating with a silanereagent (e.g., triethylsilane, etc.) in a suitable solvent (e.g.,acetonitrile, dichloromethane, etc.), in the presence of an acid (e.g.,a Lewis acid such as boron trifluoride.diethyl ether complex, etc., anda strong organic acid such as trifluoroacetic acid, methanesulfonicacid, etc.), or by treating with a hydrazine in a suitable solvent(e.g., ethylene glycol, etc.) in the presence of a base (e.g., potassiumhydroxide, etc.).

(3) Among the compounds of the formula VII, the compound wherein X is acarbon atom and Y is —CH₂— may be prepared by a method as shown in thefollowing scheme:

wherein R¹⁷ is a lower alkyl group, and the other symbols are as definedabove.

The compound of the formula VII-c may be prepared by coupling thecompound of the formula XXXV with the compound of the formula XXXIV togive the compound of the formula XXX, and subsequently by reducing theobtained compound.

The coupling reaction may be carried out in a manner similar to Step(a). Namely, the compound of the formula (XXV) is lithiated with analkyllithium (e.g., tert-butyl lithium, n-butyl lithium, etc.) in asuitable solvent (e.g., diethyl ether, tetrahydrofuran, etc.), andsubsequently, by reacting the resultant with the compound (XXIV).

The reduction reaction may be carried out in a manner similar to Step(a). Namely, it can be carried out by treating the compound of formulaXXX with a silane reagent (e.g., triethylsilane, etc.) in a suitablesolvent (e.g., acetonitrile, dichloromethane, etc.), in the presence ofan acid (e.g., boron trifluoride.diethyl ether complex, etc). (4) Amongthe compound of the formula VII, the compound wherein X is a carbon atomand Y is —CH₂— may be prepared by a method as shown in the followingscheme:

wherein R¹⁸ is a lower alkyl group, and the other symbols are as definedabove.

Namely, the compound of the formula VII-c may be prepared by couplingthe compound of the formula XXVIII with the compound of the formulaXXXVI to give the compound of the formula XXX, and subsequently byreducing the compound.

The present process may be carried out in a manner similar to Step (3).Namely, the compound of the formula (XXVIII) is lithiated with analkyllithium (e.g., tert-butyl lithium, n-butyl lithium, etc.) in asuitable solvent (e.g., diethyl ether, tetrahydrofuran, etc.), andsubsequently, by reacting the resultant with the compound (XXXVI) togive the compound of the formula (XXX). Subsequently, the compound ofthe formula XXX is treated with a silane reagent (e.g., triethylsilane,etc.) in a suitable solvent (e.g., acetonitrile, dichloromethane, etc.)in the presence of an acid (e.g., boron trifluoride.diethyl ethercomplex, etc), to give the compound of the formula (VII-c).

The compound of the formula XIV wherein Ring A is a benzene ring isdisclosed in WO 01/27128 pamphlet.

The compound of the formula VI is disclosed in WO 01/27128 or Benhaddu,S. Czernecki et al., Carbohydr. Res., vol. 260, p. 243-250, 1994.

The compound of the formula VIII may be prepared fromD-(+)-glucono-1,5-lactone according to the method disclosed in U.S. Pat.No. 6,515,117.

The compound of the formula X and the compound of the formula XI may beprepared by the following Reaction Scheme:

wherein the symbols are as defined above.

First, the compound of the formula XXXVII is lithiated with t-butyllithium in a suitable solvent (e.g., tetrahydrofuran, etc.) undercooling (e.g., −78° C.), followed by reacting with trimethyl borate togive the compound of the formula X.

Then, the compound of the formula X is reacted with a 1,2-diol (e.g.,pinacol, etc.) or 1,3-diol (e.g., 2,4-dimethyl-2,4-pentanediol, etc.) togive the compound of the formula XI.

The other starting compounds are commercially available or are describedin WO 01/27128 or WO 2004/080990, or may easily be prepared by astandard method well known to an ordinary skilled person in this field.

Hereinafter, the present invention will be illustrated by Examples andReference Examples, but the present invention should not be construed tobe limited thereto.

Example 1 1-(β-D-glucopyranosyl)-3-(5-ethyl-2-thienylmethyl)benzene

In the above scheme, Me is a methyl group, Et is an ethyl group, TMSOand OTMS are a trimethylsilyloxy group.

(1) 3-Bromo-(5-ethyl-2-thienylmethyl)benzene 1 (211 mg) was dissolved intetrahydrofuran (2 ml)-toluene (4 ml), and the mixture was cooled to−78° C. under argon atmosphere. To the mixture was added dropwisen-butyl lithium (2.44 M hexane solution, 0.29 ml), and the mixture wasstirred at the same temperature for 30 minutes. Then, a solution of2,3,4,6-tetrakis-O-trimethylsilyl-D-glucono-1,5-lactone 2 (see U.S. Pat.No. 6,515,117) (233 mg) in toluene (5 ml) was added dropwise, and themixture was further stirred at the same temperature for one hour to givea lactol compound 3. Without isolating this compound, a solution ofmethanesulfonic acid (0.1 ml) in methanol (5 ml) was added to thereaction solution, and the mixture was stirred at room temperatureovernight. Under ice-cooling, to the mixture was added a saturatedaqueous sodium hydrogen carbonate solution, and the mixture wasextracted with ethyl acetate. The extract was washed with brine, driedover magnesium sulfate, and the solvent was evaporated under reducedpressure. The residue was purified by silica gel column chromatography(chloroform:methanol=19:1) to give a methyl ether compound 4 (136 mg) ofthe lactol. APCI-Mass m/Z 412 (M+NH₄).

(2) A solution of the above methyl ether compound 4 (100 mg) indichloromethane (5 ml) was cooled to −78° C. under argon atmosphere, andthereto were added dropwise successively triisopropylsilane (0.16 ml),and boron trifluoride.diethyl ether complex (0.10 ml). The mixture wasstirred at the same temperature for 10 minutes, and warmed. The mixturewas stirred at 0° C. for 1 hour and 20 minutes, and then further stirredat room temperature for 2 hours. Under ice-cooling, a saturated aqueoussodium hydrogen carbonate solution was added, and the mixture wasextracted with ethyl acetate. The extract was washed with brine, driedover magnesium sulfate, and the solvent was evaporated under reducedpressure. The residue was purified by silica gel column chromatography(chloroform:methanol=19:1) to give the desired1-(β-D-glucopyranosyl)-3-(5-ethyl-2-thienylmethyl)benzene 5 (59 mg).APCI-Mass m/Z 382 (M+NH₄).

Example 25-(β-D-glucopyranosyl)-1-(4-ethylphenylmethyl)-1H-pyridin-2-one

In the above scheme, tBu is a tert-butyl group, OTIPS is atriisopropylsilyloxy group, and the other symbols are as defined above.

(1) 5-Bromo-1-(4-ethylphenylmethyl)-1H-pyridin-2-one 6 (293 mg) andboronic acid ester of glucal 7 (1.0 g) were dissolved in dimethoxyethane(5 ml). To the mixture were added bis(triphenyl)phosphinepalladium(II)dichloride (35 mg) and 2M sodium carbonate (2.5 ml), andthe mixture was heated with stirring under reflux under argon atmospherefor 5 hours. The mixture was cooled to room temperature, and thereaction solution was diluted with ethyl acetate, and washed with water.The organic layer was collected, dried over magnesium sulfate, and thesolvent was evaporated under reduced pressure. The residue was purifiedby silica gel column chromatography (hexane:ethyl acetate=95:5-70:30) togive glucal derivative 8 (276 mg) as colorless powder. APCI-Mass m/Z 654(M+H).

(2) A solution of glucal derivative 8 (260 mg) in tetrahydrofuran (5 ml)was cooled to 0° C. under argon atmosphere, and thereto was addeddropwise a solution of borane.tetrahydrofuran complex (1.13 Mtetrahydrofuran solution, 1.06 ml), and the reaction solution wasstirred at the same temperature overnight. A mixture of an aqueoushydrogen peroxide solution (31%, 5.0 ml) and 3N aqueous sodium hydroxidesolution (5.0 ml) was added to the reaction solution, and the mixturewas warmed to room temperature, and stirred for 30 minutes. To themixture was added 20% aqueous sodium thiosulfate solution (30 ml), andthe mixture was extracted with ether. The extract was washed with brine,dried over magnesium sulfate, and the solvent was evaporated underreduced pressure. The residue was purified by silica gel columnchromatography (hexane:ethyl acetate=96:4-66.34) to give C-glucosidecompound 9 (59 mg) as colorless powder. APCI-Mass m/Z 672 (M+H).

(3) The above C-glucoside compound 9 (55 mg) was dissolved intetrahydrofuran (2 ml), and thereto was added tetrabutyl ammoniumfluoride (1.0 M tetrahydrofuran solution, 0.41 ml). The mixture washeated with stirring under reflux for 3 hours under argon atmosphere,and the reaction solution was cooled to room temperature. The solventwas evaporated under reduced pressure, and the residue was purified bysilica gel column chromatography (chloroform:methanol=100:0-88:12) togive the desired5-(β-D-glucopyranosyl)-1-(4-ethyl-phenylmethyl)1H-pyridin-2-one 10 (10mg) as colorless powder. APCI-Mass m/Z 376 (M+H).

Example 3 1-(β-D-glucopyranosyl)-3-(benzo[b]thiophen-2-ylmethyl)benzene

In the above scheme, Bn is a benzyl group.

(1) β-m-Bromophenyl-tetra-O-benzyl-C-glucoside 11 (see WO 01/27128)(1.00 g) was dissolved in diethyl ether (60 ml), and the mixture wascooled to −78° C. under argon atmosphere. To the mixture was addeddropwise t-butyl lithium (1.49 M pentane solution, 0.99 ml), and themixture was stirred at the same temperature for 10 minutes. Then, asolution of 2-formylbenzo[b]thiophene (286 mg) in diethyl ether (2 ml)was added dropwise, and the mixture was further stirred at the sametemperature for 30 minutes. To the reaction mixture was added asaturated aqueous ammonium chloride solution, and the mixture was warmedto room temperature. The mixture was extracted with diethyl ether, theextract was dried over magnesium sulfate, and the solvent was evaporatedunder reduced pressure. The residue was purified by silica gel columnchromatography (hexane:ethyl acetate=90:10-50:50) to give an alcoholcompound 12 (835 mg). APCI-Mass m/Z 780 (M+NH₄).

(2) A solution of the above alcohol compound 12 (820 mg) indichloromethane (15 ml) was cooled to −78° C. under argon atmosphere,and thereto were added dropwise successively triethylsilane (0.52 ml),and boron trifluoride.diethyl ether complex (0.20 ml). The reactionmixture was warmed to room temperature and stirred at the sametemperature for 30 minutes. Added thereto was a saturated aqueous sodiumhydrogen carbonate solution, and the mixture was extracted withdichloromethane. The extract was dried over magnesium sulfate, and thesolvent was evaporated under reduced pressure. The residue was purifiedby silica gel column chromatography (hexane:ethyl acetate=94:6-75:25) togive the compound 13 (703 mg). APCI-Mass m/Z 764 (M+NH₄).

(3) A solution of the above compound 13 (690 mg) in dichloromethane (20ml) was cooled to 0° C., and iodotrimethylsilane (0.66 ml) was addedthereto and the mixture was stirred at room temperature for one hour.Addition of iodotrimethylsilane and stirring at room temperature wererepeated in the same manner for 3 times. Total amount of theiodotrimethylsilane was summed up to 2.64 ml. Under ice-cooling, waterwas added to the reaction mixture, and the mixture was extracted withdiethyl ether twice, and washed with an aqueous sodium thiosulfatesolution. The extract was dried over magnesium sulfate, and the solventwas evaporated under reduced pressure. The residue was purified bysilica gel column chromatography (chloroform:methanol=100:0-89:11) togive the desired1-(β-D-glucopyranosyl)-3-(benzo[b]thiophen2-ylmethyl)benzene 14 (180mg). APCI-Mass m/Z 404 (M+NH₄).

Example 41-(β-D-glucopyranosyl)-3-(5-chloro-2-thienylmethyl)-4-methylbenzene

In the above scheme, the symbols are as defined above.

(1) A solution of 2-chlorothiophene (447 mg) in tetrahydrofuran (10 ml)was cooled to −78° C. under argon atmosphere, and thereto was addeddropwise n-butyl lithium (1.59 M hexane solution, 2.61 ml). The mixturewas stirred at the same temperature for one hour, and added dropwisethereto was a solution of 5-bromo-2-methylbenzaldehyde 15 (750 mg) intetrahydrofuran (5 ml). The mixture was stirred at the same temperaturefor 30 minutes to give a compound 16. Toluene (30 ml) was added, andfurther added dropwise thereto was n-butyl lithium (1.59 M hexanesolution, 2.37 ml). The mixture was further stirred at the sametemperature for 30 minutes, and a solution of2,3,4,6-tetrakis-O-trimethylsilyl-D-glucono1,5-lactone 2 (see U.S. Pat.No. 6,515,117) (1.76 g) in toluene (5 ml) was added dropwise, and themixture was further stirred at the same temperature for one and a halfhours to give a lactol compound 17. Subsequently, a solution ofmethanesulfonic acid (1.22 ml) in methanol (25 ml) was added to thereaction solution, and the mixture was stirred at room temperatureovernight. To the mixture was added a saturated aqueous sodium hydrogencarbonate solution, and the mixture was extracted with ethyl acetate.The extract was washed with brine, dried over sodium sulfate, and thesolvent was evaporated under reduced pressure to give a crude methylether compound 18, which was used in the subsequent step without furtherpurification.

(2) A solution of the above crude methyl ether compound 18 indichloromethane (25 ml) was cooled to −78° C. under argon atmosphere,and thereto were added dropwise successively triethylsilane (3.01 ml),and boron trifluoride.diethyl ether complex (2.39 ml). The reactionmixture was warmed to 0° C., and stirred at the same temperature for 3hours. Added thereto was a saturated aqueous sodium hydrogen carbonatesolution, and the mixture was extracted with ethyl acetate. The extractwas washed with brine, dried over sodium sulfate, and the solvent wasevaporated under reduced pressure. The residue was purified by silicagel column chromatography (chloroform:methanol=100:0-92:8) to give thedesired1-(β-D-glucopyranosyl)-3-(5-chloro-2-thienylmethyl)-4-methylbenzene 19(183 mg). APCI-Mass m/Z 402/404 (M+NH₄).

In a manner similar to the method disclosed in any of the above Examples1 to 4, the compounds shown in Table 1 below were prepared fromcorresponding starting materials. The numbers shown in a column of“preparation method” in the Table indicates the Example number,according to which the preparation was carried out.

TABLE 1

Prepa- ration APCI-Mass Examples Ring A Ring B Method (m/Z) 5

1 416/418 (M + NH₄) 6

1 396 (M + NH₄) 7

1 412 (M + NH₄) 8

1 412 (M + NH₄) 9

3 354 (M + NH₄) 10

3 388/390 (M + NH₄) 11

1 396 (M + NH₄) 12

1 430/432 (M + NH₄) 13

1 426 (M + NH₄) 14

1 382 (M + NH₄) 15

1 416/418 (M + NH₄) 16

1 442/444 (M + NH₄) 17

1 430/432 (M + NH₄) 18

2 444/446 (M + NH₄) 19

1 422/424 (M + NH₄) 20

1 478/480 (M + NH₄) 21

2 470/472 (M + NH₄) 22

1 484/486 (M + NH₄) 23

1 450/452 (M + NH₄) 24

4 436/438 (M + NH₄) 25

1 504/506 (M + NH₄) 26

2 456/458 (M + NH₄) 27

1 448/450 (M + NH₄) 28

1 464/466 (M + NH₄) 29

4 478/480 (M + NH₄) 30

1 434 (M + NH₄) 31

1 438/440 (M + NH₄) 32

1 418 (M + NH₄) 33

1 422 (M + NH₄) 34

1 422 (M + NH₄) 35

1 448 (M + NH₄) 36

1 422 (M + NH₄) 37

1 484 (M + NH₄) 38

1 472 (M + NH₄) 39

1 418 (M + NH₄) 40

1 422 (M + NH₄) 41

2 418 (M + NH₄) 42

1 418 (M + NH₄) 43

1 452/454 (M + NH₄) 44

1 452/454 (M + NH₄) 45

1 472/474 (M + NH₄) 46

1 466/468 (M + NH₄) 47

1 418 (M + NH₄) 48

1 468/470 (M + NH₄) 49

1 472/474 (M + NH₄) 50

2 506/508 (M + NH₄) 51

2 438/440 (M + NH₄) 52

2 456/458 (M + NH₄) 53

2 440 (M + NH₄) 54

2 438/440 (M + NH₄) 55

1 468/470 (M + NH₄) 56

1 468/470 (M + NH₄) 57

2 456/458 (M + NH₄) 58

1 470/472 (M + NH₄) 59

2 456/458 (M + NH₄) 60

2 456/458 (M + NH₄) 61

2 472/474 (M + NH₄) 62

2 440 (M + NH₄) 63

4 452/454 (M + NH₄) 64

2 438/440 (M + NH₄) 65

1 432 (M + NH₄) 66

2 472 (M + NH₄) 67

1 464/466 (M + NH₄) 68

1 478/480 (M + NH₄) 69

1 482/484 (M + NH₄) 70

1 482/484 (M + NH₄) 71

1 508/510 (M + NH₄) 72

1 508/510 (M + NH₄) 73

1 508/510 (M + NH₄) 74

1 448 (M + NH₄) 75

1 492 (M + NH₄) 76

1 492 (M + NH₄) 77

1 466 (M + NH₄) 78

1 482/484 (M + NH₄) 79

1 492 (M + NH₄) 80

1 466 (M + NH₄) 81

1 466 (M + NH₄) 82

1 444 (M + NH₄) 83

1 462 (M + NH₄) 84

1 462 (M + NH₄) 85

2 460 (M + NH₄) 86

1 458 (M + NH₄) 87

1 478/480 (M + NH₄) 88

1 498/500 (M + NH₄) 89

1 478/480 (M + NH₄) 90

1 474 (M + NH₄) 91

2 426 (M + H) 92

2 440 (M + H) 93

2 382 (M + NH₄) 94

2 382 (M + NH₄) 95

2 382 (M + NH₄) 96

2 382 (M + NH₄) 97

2 416/418 (M + NH₄) 98

2 416/418 (M + NH₄) 99

1 404 (M + NH₄) 100

1 366 (M + NH₄) 101

1 388 (M + NH₄) 102

1 422/424 (M + NH₄)

Example 1031-(β-D-glucopyranosyl)-3-(benzothiazol-2-ylmethyl)-4-methylbenzene

In the above scheme, the symbols are as defined above.

(1) 1-(benzothiazol-2-ylmethyl)-5-bromo-2-methylbenzene 20 (495 mg) wasdissolved in tetrahydrofuran (5 ml)-toluene (10 ml), and the mixture wascooled to −78° C. under argon atmosphere. To the mixture was addeddropwise n-butyl lithium (2.44 M hexane solution, 0.67 ml), andsuccessively was added dropwise t-butyl lithium (2.44 M pentanesolution, 1.57 ml). The mixture was stirred at the same temperature for10 minutes, and then, a solution of2,3,4,6-tetrakis-O-trimethylsilyl-D-glucono1,5-lactone 2 (see U.S. Pat.No. 6,515,117) (2.17 g) in toluene (5 ml) was added dropwise, and themixture was further stirred at the same temperature for 15 minutes togive a lactol compound 21. Without isolating this compound, a solutionof methanesulfonic acid (1.5 ml) in methanol (25 ml) was added to thereaction solution, and the mixture was stirred at room temperatureovernight. Under ice-cooling, to the mixture was added a saturatedaqueous sodium hydrogen carbonate solution, and the mixture wasextracted with ethyl acetate. The extract was washed with brine, driedover magnesium sulfate, and the solvent was evaporated under reducedpressure to give a methyl ether compound 22, which was used in thesubsequent step without further purification.

(2) A solution of the above methyl ether compound 22 in dichloromethane(20 ml)-acetonitrile (10 ml) was cooled to −78° C. under argonatmosphere, and thereto were added dropwise successively triethylsilane(1.24 ml), and boron trifluoride.diethyl ether complex (0.99 ml). Themixture was warmed to room temperature and stirred at the sametemperature for 30 minutes. Under ice-cooling, a saturated aqueoussodium hydrogen carbonate solution was added, and the solvent wasevaporated under reduced pressure. The residue was extracted with ethylacetate. The extract was washed with brine, dried over magnesiumsulfate, and the solvent was evaporated under reduced pressure. Theresidue was purified by silica gel column chromatography(chloroform:methanol=100:0-85:15) to give1-(β-D-glucopyranosyl)-3-(benzothiazol-2-ylmethyl)-4-methylbenzene 23(200 mg) as colorless powder. APCI-Mass m/Z 402 (M+H).

In a manner similar to Examples 103, the compounds shown in Table 2below were prepared from corresponding starting materials.

TABLE 2

APCI- Ex- Mass amples Ring A Ring B (m/Z) 104

422/424 (M + H) 105

480/482 (M + NH₄)

Example 1061-(β-D-glucopyranosyl)-4-chloro-3-(1-oxy-benzo[b]thiophen-2-ylmethyl)benzene

In the above scheme, AcO and OAc are an acetyloxy group.

(1) The compound 24 (9.61 g) obtained in Example 31 was dissolved inchloroform (100 ml), and to the mixture were added acetic anhydride(21.6 ml), pyridine (18.5 ml), and 4-dimethylaminopyridine (128 mg), andthe mixture was stirred at room temperature for 3.5 days. Then,Chloroform was evaporated under reduced pressure, and the residue wasdissolved in ethyl acetate (200 ml). The solution was washedsuccessively with 10% aqueous hydrochloric acid solution, water, asaturated aqueous sodium hydrogen carbonate solution, and brine, driedover magnesium sulfate, and treated with activated carbon. The solventwas evaporated under reduced pressure, and the residue was crystallizedfrom ethanol to give a tetraacetate compound 25 (6.14 g). APCI-Mass m/Z606/608 (M+NH₄).

(2) The above tetraacetate compound 25 (1.00 g) was dissolved indichloromethane (20 ml), and under ice-cooling, m-chloroperbenzoic acid(439 mg) was added thereto, and the mixture was stirred a roomtemperature overnight. m-Chloroperbenzoic acid was further addedthereto, and the mixture was stirred again at room temperatureovernight. The reaction mixture was washed successively with 10% aqueoussodium thiosulfate solution, a saturated aqueous sodium hydrogencarbonate solution, and brine. The mixture was dried over magnesiumsulfate, and the solvent was evaporated under reduced pressure. Theresidue was purified by silica gel column chromatography (hexane:ethylacetate=2:1-1:2) to give a sulfoxide compound 26 (295 mg). APCI-Mass m/Z622/624 (M+NH₄).

(3) The above sulfoxide compound 26 (293 mg) was dissolved in a mixtureof methanol (10 ml)-tetrahydrofuran (5 ml), and sodium methoxide (28%methanol solution, 2 drops) was added thereto, and the mixture wasstirred at room temperature for one hour. The solvent was evaporatedunder reduced pressure, and the residue was purified by silica gelcolumn chromatography (chloroform:methanol=9:1) to give1-(β-D-glucopyranosyl)-4-chloro-3-(1-oxybenzo[b]thiophen-2-ylmethyl)benzeneas pale yellow powder. APCI-Mass m/Z 454/456 (M+NH₄).

Example 1071-(β-D-glucopyranosyl)-4-chloro-3-(1,1-dioxy-benzo[b]thiophen-2-ylmethyl)benzene

The target compound was prepared in a manner similar to Example 106.APCI-Mass m/Z 470/472 (M+NH₄).

Example 1083,5-dimethyl-4-(4-ethylphenylmethyl)-1-(β-D-glucopyranosyl)pyrazole

In the above scheme, the symbols are as defined above.

(1) 3-(4-ethylphenylmethyl)-2,4-pentanedione 28 (700 mg) and2,3,4,6-tetra-O-benzyl-α,β-D-glucosehydrazone 29 (1.70 g) (See Schmidt,R. R. et al., Liebigs Ann. Chem. 1981, 2309) were dissolved intetrahydrofuran (20 ml), and the mixture was stirred at room temperaturefor 18 hours under argon atmosphere. The solvent was evaporated underreduced pressure, and the residue was dissolved in toluene (20 ml), andthe mixture was heated with stirring under reflux for 2 hours. Themixture was left alone until it was cooled, and the solvent wasevaporated under reduced pressure. The residue was purified by silicagel column chromatography (hexane:ethyl acetate=90:10-65:35) to give3,5-dimethyl-4-(4-ethylphenylmethyl)-1-(2,3,4,6-tetra-O-benzyl-β-D-glucopyranosyl)pyrazole30 (299 mg) as a pale yellow semisolid. APCI-Mass m/Z 737 (M+H).

(2) The above tetrabenzyl compound 30 (294 mg) was dissolved in amixture of ethanol (5 ml) and tetrahydrofuran (4 ml), and added theretowas palladium hydroxide (100 mg), and the mixture was stirred at roomtemperature for 16 hours under hydrogen atmosphere under normalpressure. Insoluble materials were filtered off, and the solvent wasevaporated under reduced pressure. The residue was crystallized fromdiethyl ether to give the desired3,5-dimethyl-4-(4-ethylphenylmethyl)-1-(β-D-glucopyranosyl)pyrazole 31(118 mg) as colorless powder. APCI-Mass m/Z 377 (M+H).

Example 1094-(4-ethylphenylmethyl)-1-(β-D-glucopyranosyl)-1,2,3-triazole

In the above scheme, n-Bu is n-butyl group, and other symbols are asdefined above.

(1) A solution of4-(bromomethyl)-1-(2,3,4,6-tetra-O-acetyl-β-D-glucopyranosyl)-1,2,3-triazole32 (500 mg) (See Federico G. H. et al., J. Med. Chem. (1979) 29, 496),tri-n-butyl(4-ethylphenyl)tin 33 (604 mg) andtetrakis(triphenylphosphine)palladium (0) (59 mg) in tetrahydrofuran (10ml) was stirred under heating at 70° C. for 12 hours under argonatmosphere. The reaction mixture was cooled to room temperature, dilutedwith ethyl acetate, and then, an aqueous potassium fluoride solution wasadded thereto and the mixture was stirred at room temperature for onehour. Insoluble materials were filtered off, and the filtrate was washedwith water, and dried over magnesium sulfate. The solvent was evaporatedunder reduced pressure. The residue was purified by silica gel columnchromatography (hexane:ethyl acetate=90:10-50:50) to give4-(4-ethylphenylmethyl)-1-(2,3,4,6-tetra-O-acetyl-β-D-glucopyranosyl)-1,2,3-triazole34 (90 mg) as a colorless solid. APCI-Mass m/Z 518 (M+H).

(2) From the above tetraacetate compound 34, the desired4-(4-ethylphenylmethyl)-1-(β-D-glucopyranosyl)1,2,3-triazole 35 wasprepared in a manner similar to Example 106-(3) as a colorless solid.APCI-Mass m/Z 350 (M+H).

Example 110 4-(4-Ethylphenylmethyl)-1-(β-D-glucopyranosyl)pyrazole

In the above scheme, TMS is a trimethylsilyl group, and other symbolsare as defined above.

(1) To a solution of 4-(4-ethylphenylmethyl)pyrazole 36 (495 mg) inacetonitrile (2.0 ml) was added N,O-bis(trimethylsilyl)acetamide (1.05ml), and the mixture was stirred under heating at 60° C. for 2.5 hoursunder argon atmosphere. The reaction mixture was cooled to roomtemperature, and the solvent was evaporated under reduced pressure togive crude 4-(4-ethylphenylmethyl)-1-trimethylsilylpyrazole 37, whichwas used in the subsequent reaction without further purification.

(2) The above N-silyl compound 37 was dissolved in dichloroethane (7.0ml), and added thereto were molecular sieve 4A powder (500 mg),1,2,3,4,6-penta-O-acetyl-β-D-glucopyranose 38 (1.04 g) andtrimethylsilyl trifluoromethanesulfonate (0.51 ml). The mixture wasstirred under heating at heating at 80° C. for 3 hours under argonatmosphere. The reaction mixture was cooled to room temperature, andinsoluble materials were filtered off. Subsequently, the filtrate waspoured into a saturated aqueous sodium hydrogen carbonate solution. Themixture was extracted twice with dichloromethane, and dried over sodiumsulfate. The solvent was evaporated under reduced pressure, and theresidue was purified by silica gel column chromatography (hexane:ethylacetate=80:20-50:50) to give4-(4-ethylphenylmethyl)-1-(2,3,4,6-tetra-O-acetyl-β-D-glucopyranosyl)pyrazole39 (610 mg) as a colorless semisolid. APCI-Mass m/Z 517 (M+H).

(3) From the above tetraacetate compound 39, the desired4-(4-ethylphenylmethyl)-1-(β-D-glucopyranosyl)pyrazole 40 was preparedin a manner similar to Example 106-(3) as colorless oil. APCI-Mass m/Z349 (M+H).

In a manner similar to Example 110, the compounds shown in Table 3 belowwere prepared from corresponding starting materials.

TABLE 3

APCI-Mass Examples Ring A (m/Z) 111

363 (M + H) 112

363 (M + H) 113

376 (M + H) 114

393 (M + NH₄) 115

415 (M + NH₄) 116

399 (M + H) 117

399 (M + H)

Example 1183-RS-(4-ethylphenylmethyl)-1-(β-D-gluco-pyranosyl)-2,3-dihydroindole

In the above scheme, the symbols are as defined above.

(1) To a suspension of potassium hydroxide power (953 mg) and sodiumsulfate (6.0 g) in acetonitrile (50 ml) was added3-(4-ethylphenylmethy)-1H-indole 41 (500 mg), and the mixture wasstirred at room temperature for one hour under argon atmosphere. To thereaction mixture was added a solution of benzylchloro-α-D-glucose 42(3.0 g) (see Cicchillo R. M. et al., Carbohydrate Research (2000) 328,431) in acetonitrile (20 ml), and the mixture was stirred at roomtemperature overnight. The reaction mixture was poured into 2N aqueoushydrochloric acid solution, and the mixture was extracted with diethylether. The extract was washed with brine, dried over magnesium sulfate,and the solvent was evaporated under reduced pressure. The residue waspurified by silica gel column chromatography (hexane:ethylacetate=100:0-85:15) to give3-(4-ethylphenylmethyl)-1-(2,3,4,6-tetra-O-benzyl-αβ-D-glucopyranosyl)-1H-indole43 (1.04 g) as a pale yellow syrup. APCI-Mass m/Z 758 (M+H).

(3) From the above tetrabenzyl compound 43, the desired3-RS-(4-ethylphenylmethyl)-1-(β-D-glucopyranosyl)-2,3-dihydroindole 44was prepared in a manner similar to Example 108-(2) as pale pink powder.APCI-Mass m/Z 400 (M+H).

Example 1191-(β-D-glucopyranosyl)-4-chloro-3-(5-(2-pyrimidinyl)-2-thienylmethyl)benzene

In the above scheme, the symbols are as defined above.

(1) To a solution of 5-bromo-2-chlorobenzoic acid 45 (1.22 g) in amixture of tetrahydrofuran (20 ml)-toluene (20 ml) was added dropwisen-butyl lithium (2.44 M hexane solution, 4.26 ml) at −78° C. under argonatmosphere. The mixture was stirred at −78° C. for 30 minutes, and addeddropwise thereto was a solution of2,3,4,6-tetra-O-benzyl-β-D-glucolactone 46 (2.16 g) in toluene (10 ml),and the mixture was further stirred at the same temperature for 2 hours.To the mixture was added a saturated aqueous ammonium chloride solution,and the mixture was warmed to room temperature. The reaction mixture wasmade acidic by addition of 10% aqueous hydrochloric acid solution, andextracted with ethyl acetate. The extract was washed with brine, anddried over magnesium sulfate. The solvent was evaporated under reducedpressure to give a crude compound 47 as oil, which was used in thesubsequent step without further purification.

(2) The above crude compound 47 was dissolved in dichloromethane (30ml), and thereto were added dropwise triisopropylsilane (2.46 ml) andboron trifluoride.diethyl ether complex (1.52 ml) at −78° C.Subsequently, the mixture was stirred at 0° C. for one hour, and addedthereto was a saturated aqueous sodium hydrogen carbonate solution, andthe mixture was further stirred for 20 minutes. The reaction mixture wasmade acidic by addition of 10% aqueous hydrochloric acid solution, andextracted with ethyl acetate. The extract was washed with brine, anddried over magnesium sulfate. The solvent was evaporated under reducedpressure, and the residue was purified by silica gel chromatography(chloroform:methanol=100:1-50:1) to give a compound 48 (1.41 g) as oil.

(3) The compound 48 (1.41 g) was dissolved in dichloromethane (10 ml),and added thereto was oxalyl chloride (2 ml). The mixture was stirred atroom temperature for 3 hours. The solvent was evaporated under reducedpressure to give a corresponding acid chloride. The compound wasdissolved in chloroform (10 ml), and added dropwise to a solution ofN,O-dimethylhydroxyamine hydrochloride (390 mg) and triethyl amine (1.12ml) in chloroform (10 ml) at 0° C. The mixture was stirred at roomtemperature overnight, and the reaction mixture was washed successivelywith 10% aqueous hydrochloric acid solution, water, a saturated aqueoussodium hydrogen carbonate solution and brine. The mixture was dried overmagnesium sulfate, and the solvent was evaporated under reducedpressure. The residue was purified by silica gel column chromatography(hexane:ethyl acetate=4:1-2:1) to give a compound 49 (784 mg) as paleyellow oil. APCI-Mass m/Z 739/741 (M+NH₄).

(4) The compound 49 (1.22 g) was dissolved in tetrahydrofuran (20 ml),and the mixture was cooled to −78° C. under argon atmosphere. To themixture was added dropwise diisobutylaluminum hydride (1.0 M toluenesolution, 4.2 ml), and the mixture was stirred at the same temperaturefor 3 hours. Added thereto was 10% aqueous hydrochloric acid solution,and the mixture was extracted with ethyl acetate. The extract was washedsuccessively with a saturated aqueous sodium hydrogen carbonate solutionand brine. The extract was dried over magnesium sulfate and the solventwas evaporated under reduced pressure. The residue was purified bysilica gel column chromatography (hexane:ethyl acetate=9:1) to give acompound 50 (771 mg) as pale yellow oil. APCI-Mass m/Z 680/682 (M+NH₄).

(5) 2,5-dibromothiophene 51 (1.31 g) was dissolved in tetrahydrofuran(30 ml) and the mixture was cooled to −78° C. under argon atmosphere. Tothe mixture was added dropwise n-butyl lithium (2.59 M hexane solution,2.01 ml), and the mixture was stirred at the same temperature for 30minutes. Added dropwise thereto was a solution of the above compound 50(2.40 g) in tetrahydrofuran (15 ml), and the mixture was stirred at −78°C. for 2 hours. Added thereto was a saturated aqueous ammonium chloridesolution, and the mixture was extracted with ethyl acetate and washedwith brine. The extract was dried over magnesium sulfate and the solventwas evaporated under reduced pressure. The residue was purified bysilica gel column chromatography (hexane:ethyl acetate=9:1-4:1) to givea compound 52 (2.62 mg) as pale brown oil. APCI-Mass m/Z 842/844(M+NH₄).

(6) The compound 52 was treated in a manner similar to Example 3-(2) togive1-(2,3,4,6-tetra-O-benzyl-β-D-glucopyranosyl)-3-(5-bromo-2-thienylmethyl)-4-chlorobenzene53 as a pale yellow solid. APCI-Mass m/Z 826/828 (M+NH₄).

(7) A mixed solution of the above1-(2,3,4,6-tetra-O-benzyl-β-D-glucopyranosyl)-3-(5bromo-2-thienylmethyl)-4-chlorobenzene53 (200 mg), tri-n-butyl(2-pyrimidinyl)tin 54 (137 mg) andbis(triphenylphosphine)palladium(II)dichloride (9 mg) inN-methyl-2-pyrrolidinone (5 ml) was stirred at 100° C. four 7 hoursunder argon atmosphere. The mixture was cooled to room temperature, andwater was added thereto, and the mixture was extracted with ethylacetate. The extract was washed with water and subsequently with brine,and dried over magnesium sulfate. The solvent was evaporated underreduced pressure. The residue was purified by silica gel columnchromatography (hexane:ethyl acetate=4:1-2:1) to give1-(2,3,4,6-tetra-O-benzyl-β-D-glucopyranosyl)-4-chloro-3-(5-(2-pyrimidinyl)-2-thienylmethyl)benzene55 (93 mg) as pale brown oil. APCI-Mass m/Z 826/828 (M+NH₄).

(8) To a solution of the above1-(2,3,4,6-tetra-O-benzyl-β-D-glucopyranosyl)-4-chloro-3-(5(2-pyrimidinyl)-2-thienylmethyl)benzene55 (90 mg) in ethanethiol (1.5 ml) was added boron trifluoride.ethercomplex (0.42 ml) at 0° C., and the mixture was stirred at roomtemperature overnight. The mixture was cooled again to 0° C., and addedthereto were a saturated aqueous sodium hydrogen carbonate solution andan aqueous sodium thiosulfate solution. The mixture was extracted withethyl acetate and tetrahydrofuran, and the extract was dried overmagnesium sulfate. The solvent was evaporated under reduced pressure.The residue was purified by silica gel column chromatography(chloroform:methanol=19:1-9:1) to give the desired1-(β-D-glucopyranosyl)-4-chloro-3-(5-(2-pyrimidinyl)-2-thienylmethyl)benzene56 (27 mg) as pale yellow powder. APCI-Mass m/Z 449/451 (M+H).

Example 1201-(β-D-glucopyranosyl)-3-(5-(6-fluoro-3-pyridyl)-2-thienylmethyl)-4-methylbenzene

In the above scheme, the symbols are as defined as above.

(1) The compound 19 obtained in Example 4 was treated in a mannersimilar to Example 106-(1) to give1-(2,3,4,6-tetra-O-acetyl-β-D-glucopyranosyl)-3-(5-chloro-2-thienylmethyl)-4-methylbenzene57 as colorless crystals. APCI-Mass m/Z 570/572 (M+NH₄).

(2) A solution of the above1-(2,3,4,6-tetra-O-acetyl-β-D-glucopyranosyl)-3-(5-chloro-2-thienylmethyl)-4-methylbenzene(200 mg), 6-fluoropyridine-3-boronic acid 58 (117 mg),tri-tert-butylphosphine.tetrafluoroboric acid adduct (24 mg), potassiumfluoride (80 mg) and tris(dibenzylideneacetone)dipalladium (0) (27 mg)in tetrahydrofuran (8 ml) was stirred at room temperature for 2 daysunder argon atmosphere. Added thereto was a saturated aqueous ammoniumchloride solution and the mixture was extracted with ethyl acetate. Theextract was dried over magnesium sulfate. The solvent was evaporatedunder reduced pressure and the residue was purified by silica gel columnchromatography (hexane:ethyl acetate=90:10-70:30) to give1-(2,3,4,6-tetra-O-acetyl-β-D-glucopyranosyl)-3-(5(6-fluoro-3-pyridyl)-2-thienylmethyl)-4-methylbenzene59 (44 mg) as colorless crystals. APCI-Mass m/Z 631 (M+NH₄).

(3) The above1-(2,3,4,6-tetra-O-acetyl-β-D-glucopyranosyl)-3-(5(6-fluoro-3-pyridyl)-2-thienylmethyl)-4-methylbenzene59 (39 mg) was dissolved in 1,4-dioxane (4 ml)-tetrahydrofuran (4 ml),and added thereto was 2N sodium hydroxide (2 ml). The mixture wasstirred at room temperature for one hour. The mixture was made acidic byaddition of an aqueous citric acid solution, and the mixture wasextracted with ethyl acetate. The extract was washed successively with asaturated aqueous sodium hydrogen carbonate solution and brine, and thendried over sodium sulfate. The solvent was evaporated under reducedpressure to give the desired1-(β-D-glucopyranosyl)-3-(5-(6-fluoro-3-pyridyl)-2-thienylmethyl)-4-methylbenzene60 (34 mg) as colorless powder. APCI-Mass m/Z 463 (M+NH₄).

Example 1211-(β-D-glucopyranosyl)-4-chloro-3-(2-(5-phenyl-2-thienyl)ethyl)benzene

The target compound was obtained in a manner similar to Example 1, from5-bromo-2-chloro-1-(2-(5-phenyl-2-thienyl)ethyl)benzene. APCI-Mass m/Z478/480 (M+NH₄).

Example 1221-(β-D-glucopyranosyl)-3-(5-(3-dimethylaminophenyl)-2-thienylmethyl)-4-methylbenzene

(1)1-(2,3,4,6-tetra-O-acetyl-β-D-glucopyranosyl)-3-(5-chloro-2-thienylmethyl)-4-methylbenzene57 obtained in Example 120 (1) and 3-dimethylaminophenylboronic acidwere used and treated in a manner similar to Example 120-(2) to give1-(2,3,4,6-tetra-O-acetyl-β-D-glucopyranosyl)-3-(5-(3-dimethylaminophenyl)-2-thienylmethyl)-4-methylbenzene.APCI-Mass m/Z 638 (M+H).

(2) the above1-(2,3,4,6-tetra-O-acetyl-β-D-glucopyranosyl)-3-(5-(3-dimethylaminophenyl)-2-thienylmethyl)-4-methylbenzenewas treated in a manner similar to Example 106-(3) to give the targetcompound. APCI-Mass m/Z 470 (M+H).

Example 1231-(β-D-glucopyranosyl)-4-chloro-3-(5-(3-cyanophenyl)-2-thienylmethyl)benzene

(1) A mixed solution of1-(2,3,4,6-tetra-O-benzyl-β-D-glucopyranosyl)-3-(5-bromo-2-thienylmethyl)-4-chlorobenzene53 (1.24 g) obtained in Example 119-(6), 3-cyanophenylboronic acid (270ml), bis(triphenylphosphine)palladium (II)dichloride (54 mg) and 2Maqueous sodium carbonate solution (2.3 ml) in 1,2-dimethoxyethane (12ml) was heated under reflux for 4 hours. The mixture was diluted withethyl acetate and washed successively with a saturated aqueous sodiumhydrogen carbonate solution and brine. The mixture was dried over sodiumsulfate, and the solvent was evaporated under reduced pressure. Theresidue was purified by silica gel column chromatography (hexane:ethylacetate=7:1-5:1) to give1-(2,3,4,6-tetra-O-benzyl-β-D-glucopyranosyl)-4-chloro-3-(5-(3-cyanophenyl)-2-thienylmethyl)benzene(1.12 g) as colorless oil. APCI-Mass m/Z 849/851 (M+NH₄).

(2) The above1-(2,3,4,6-tetra-O-benzyl-β-D-glucopyranosyl)-4-chloro-3-(5-(3-cyanophenyl)-2-thienylmethyl)benzenewas used and treated in a manner similar to Example 3-(3) to give thetarget compound as colorless powder. APCI-Mass m/Z 489/491 (M+NH₄).

Example 1241-(β-D-glucopyranosyl)-4-methyl-3-(5-(5-pyrimidinyl)-2-thienylmethyl)benzene

(1) A mixed solution of1-(2,3,4,6-tetra-O-acetyl-β-D-glucopyranosyl)-3-(5-chloro-2-thienylmethyl)-4-methylbenzene57 (600 mg) obtained in Example 120-(1), tri-n-butyl(5-pyrimidinyl)tin(600 mg), tri-tert-butylphosphine.tetrafluoroboric acid adduct (116 mg),cesium fluoride (414 mg), and tris(dibenzylideneacetone)dipalladium (0)(91 mg) in 1,4-dioxane (18 ml) was heated under reflux at 100° C. for 3hours under argon atmosphere. Insoluble materials were filtered off, andthe filtrate was diluted with ethyl acetate and washed with brine. Thesolvent was evaporated under reduced pressure, and the residue waspurified by silica gel column chromatography (hexane:ethylacetate=75:25-40:60) to give1-(2,3,4,6-tetra-O-acetyl-β-D-glucopyranosyl)-4-methyl-3-(5(5-pyrimidinyl)-2-thienylmethyl)benzene(266 mg) as colorless crystals. APCI-Mass m/Z 597 (M+H).

(2) The above1-(2,3,4,6-tetra-O-acetyl-β-D-glucopyranosyl)-4-methyl-3-(5(5-pyrimidinyl)-2-thienylmethyl)benzenewas used and treated in a manner similar to Example 106-(3) to give thetarget compound as colorless powder. APCI-Mass m/Z 429 (M+H).

Example 1251-(β-D-glucopyranosyl)-4-chloro-3-(2-phenyl-5-thiazolylmethylbenzene

The target compound was prepared in a manner similar to Example 1,starting from 5-bromo-2-chloro-1-(2-phenyl-5-thiazolylmethyl)benzene.APCI-Mass m/Z 448/450 (M+H).

Example 1261-(β-D-glucopyranosyl)-4-chloro-3-(5-(3-pyridyl)-2-thienylmethyl)benzene

(1) 1-(β-D-glucopyranosyl)-4-chloro-3-(5-chloro-2-thienylmethyl)benzeneobtained in Example 19 was used and treated in a manner similar toExample 106-(1) to give1-(2,3,4,6-tetra-O-acetyl-β-Dglucopyranosyl)-4-chloro-3-(5-chloro-2-thienylmethyl)benzeneas colorless crystals. APCI-Mass m/Z 590/592 (M+NH₄).

(2) The above1-(2,3,4,6-tetra-O-acetyl-β-D-glucopyranosyl)-4-chloro-3-(5-chloro-2-thienylmethyl)benzeneand tri-n-butyl(3-pyridyl)tin were used and treated in a manner similarto Example 124 to give the target compound as colorless powder.APCI-Mass m/Z 448/450 (M+H).

Example 1271-(β-D-glucopyranosyl)-3-(5-(3-cyanophenyl)-2-thienylmethyl)-4-methylbenzene

(1)1-(2,3,4,6-tetra-O-acetyl-β-D-glucopyranosyl)-3-(5-chloro-2-thienylmethyl)-4-methylbenzene57 obtained in Example 120-(1) and 3-cyanophenylboronic acid were usedand treated in a manner similar to Example 120-(2) to give1-(2,3,4,6-tetra-O-acetyl-β-D-glucopyranosyl)-3-(5-(3-cyanophenyl)-2-thienylmethyl)-4-methylbenzene. APCI-Mass m/Z 637 (M+NH₄).

(2) The above1-(2,3,4,6-tetra-O-acetyl-β-D-glucopyranosyl)-3-(5-(3-cyanophenyl)-2-thienylmethyl)-4-methylbenzenewas used and treated in a manner similar to Example 106-(3) to give thetarget compound as colorless powder. APCI-Mass m/Z 469 (M+NH₄).

Example 1281-(β-D-glucopyranosyl)-4-chloro-3-(5-pyrazinyl-2-thienylmethyl)benzene

In the above scheme, the symbols are as defined above.

(1) A solution of mesityl bromide (4.74 g) in tetrahydrofuran (100 ml)was cooled to −78° C. under argon atmosphere, and thereto was addeddropwise t-butyl lithium (1.43 M pentane solution, 33 ml). The mixturewas stirred at −30 to −20° C. for one hour, and then, a mixed solutionof t-butyl 5-bromo-2-chlorobenzoate 61 (4.94 g) and2,3,4,6-tetrakis-O-trimethylsilyl-D-glucono-1,5-lactone 2 (see U.S. Pat.No. 6,515,117) (11.10 g) in tetrahydrofuran (70 ml) was added dropwisethereto at −78° C. The mixture was stirred at the same temperature forone hour to give a compound 62. Without isolating this compound, asolution of methanesulfonic acid (3.75 ml) in methanol (50 ml) was addedto the reaction solution, and the mixture was stirred at roomtemperature for 18 hours. To the mixture was added a saturated aqueoussodium hydrogen carbonate solution at 0° C., and the mixture wasextracted with ethyl acetate twice. The extract was washed with brine,dried over magnesium sulfate, and the solvent was evaporated underreduced pressure. The residue was purified by silica gel columnchromatography (chloroform:methanol=19:1) to give a methyl ethercompound 63 (4.55 g) of the lactol as pale yellow powder. APCI-Mass m/Z422/424 (M+NH₄).

(2) The compound 63 was treated in a manner similar to Example 106-(1)to give the compound 64. APCI-Mass m/Z 590/592 (M+NH₄).

(3) A solution of the above compound 64 (7.10 g) in formic acid (50 ml)was stirred at 50° C. for 30 minutes. The solvent was evaporated underreduced pressure, and the residue was subjected to azeotropicdistillation with toluene, twice, to give a compound 65 as colorlesspowder. Without further purification, this compound was dissolved indichloromethane (50 ml). Added thereto were oxalyl chloride (1.3 ml) andN,N-dimethylformamide (one drop), and the mixture was stirred at roomtemperature overnight. The solvent was evaporated under reduced pressureto give a corresponding acid chloride, which was dissolved indichloroethane (50 ml), without further purification. To the solutionwas added 2-bromothiophene 66 (2.63 g) and the mixture was cooled to 0°C. Added gradually thereto was aluminum chloride (8.26 g), andsubsequently, the mixture was stirred at the same temperature for 30minutes. The reaction mixture was poured into ice-cold water, and themixture was extracted with ethyl acetate. The extract was washedsuccessively with water, a saturated aqueous sodium hydrogen carbonatesolution and brine, dried over sodium sulfate, and the solvent wasevaporated under reduced pressure. The residue was purified by silicagel column chromatography (hexane:ethyl acetate=10:1-5:1) to give acompound 67 (7.01 g) as pale yellowish powder. APCI-Mass m/Z 678/680(M+NH₄).

(4) The above ketone compound 67 (7.01 g) was dissolved in ethanol (50ml), and thereto was added sodium borohydride (401 mg), and the mixturewas stirred at room temperature for 30 minutes. The solvent wasevaporated under reduced pressure, and the residue was dissolved inethyl acetate. The solution was washed with successively with water, 2Naqueous hydrochloride acid solution, a saturated aqueous sodium hydrogencarbonate solution and brine, and dried over sodium sulfate. The solventwas evaporated under reduced pressure to give a compound 68 as paleyellow powder, which was dissolved in methanol (50 ml) without furtherpurification. To the solution, sodium methoxide (28% methanol solution,5 drops) was added, and then the mixture was stirred at room temperaturefor 2.5 hours. The solvent was evaporated under reduced pressure to givea deacetylated compound 69 as pale yellow powder. Without furtherpurification, it was dissolved in dichloromethane (170 ml)-acetonitrile(70 ml), and added thereto was triethylsilane (10.2 ml), and the mixturewas cooled to 0° C. Added dropwise thereto was boron trifluoride.diethylether complex (8.1 ml), and the mixture was stirred at room temperaturefor 5 hours. To the mixture was added a saturated aqueous sodiumhydrogen carbonate solution, and the mixture was extracted with ethylacetate, and the extract was dried over magnesium sulfate. The solventwas evaporated under reduced pressure to give a crude1-(β-D-glucopyranosyl)-3-(5-bromo-2-thienylmethyl)-4-chlorobenzene 70 aspale brown powder. Without further purification, this was dissolved indichloromethane (30 ml), and added thereto were acetic anhydride (10.0ml), pyridine (8.57 ml) and 4-dimethylaminopyridine (258 mg), and themixture was stirred at room temperature for one hour. The solvent wasevaporated under reduced pressure, and the residue was dissolved inethyl acetate, and the solution was washed successively with water, 1Naqueous hydrochloric acid solution, a saturated aqueous sodium hydrogencarbonate solution and brine. The solution was dried over sodiumsulfate, and the solvent was evaporated under reduced pressure. Theresidue was crystallized from methanol to give1-(2,3,4,6-tetra-O-acetyl-β-D-glucopyranosyl)-3-(5-bromo-2-thienylmethyl)-4-chlorobenzene71 (3.17 g) as colorless crystals. APCI-Mass m/Z 634/636 (M+NH₄).

(5) The above1-(2,3,4,6-tetra-O-acetyl-β-D-glucopyranosyl)-3-(5-bromo-2-thienylmethyl)-4-chlorobenzene71 (600 mg) was dissolved in 1,4-dioxane (11 ml). Added thereto weretri-n-butyl(pyrazinyl)tin 72 (720 mg),tetrakis(triphenylphosphine)palladium (0) (206 mg) and copper (I) iodide(51 mg), and the mixture was stirred under heating at 100° C. for 1.5hours, under irradiation by a microwave (500 W). The mixture was dilutedwith ethyl acetate, the insoluble materials were filtered off, and thefiltrate was washed with water. The solvent was evaporated under reducedpressure. The residue was purified by silica gel column chromatography(hexane:ethyl acetate=75:25-30:70), and crystallized from hexane-diethylether to give1-(2,3,4,6-tetra-O-acetyl-β-D-glucopyranosyl)-4-chloro-3-(5-pyrazinyl-2-thienylmethyl)benzene73 (263 mg) as pale yellow crystals. APCI-Mass m/Z 617/619 (M+H).

(6) The above1-(2,3,4,6-tetra-O-acetyl-β-D-glucopyranosyl)-4-chloro-3-(5-pyrazinyl-2-thienylmethyl)benzene73 was used and treated in a manner similar to Example 106-(3) to givethe desired1-(β-D-glucopyranosyl)-4-chloro-3-(5-pyrazinyl-2-thienylmethyl)benzene74 as colorless powder. APCI-Mass m/Z 449/451 (M+H).

Example 1291-(β-D-glucopyranosyl)-4-chloro-3-(6-ethoxybenzo[b]thiophen-2-ylmethyl)benzene

5-Bromo-2-chloro-1-(6-ethoxybenzo[b]thiophen-2-ylmethyl)-benzene wasused and treated in a manner similar to Example 1 to give the targetcompound. APCI-Mass m/Z 482/484 (M+NH₄).

Example 1301-(β-D-glucopyranosyl)-3-(5-(3-difluoromethylphenyl)-2-thienylmethyl)-4-methylbenzene

(1)1-(2,3,4,6-tetra-O-acetyl-β-D-glucopyranosyl)-3-(5-chloro-2-thienylmethyl)-4-methylbenzene57 obtained in Example 120-(1) and 3-formylphenylboronic acid were usedand treated in a manner similar to Example 120-(2) to give1-(2,3,4,6-tetra-O-acetyl-β-D-glucopyranosyl)-3-(5-(3-formylphenyl)-2-thienylmethyl)-4-methylbenzene.APCI-Mass m/Z 640 (M+NH₄).

(2) The above1-(2,3,4,6-tetra-O-acetyl-β-D-glucopyranosyl)3-(5-(3-formylphenyl)-2-thienylmethyl)-4-methylbenzene(100 mg) was dissolved in dichloromethane (2 ml), and added thereto was(diethylamino)sulfur trifluoride (0.30 ml). The mixture was stirred atroom temperature overnight. Water was added to the mixture and themixture was extracted with chloroform. The extract was washed with brineand dried over magnesium sulfate, and then, the solvent was evaporatedunder reduced pressure. The residue was purified by silica gel columnchromatography (hexane:ethyl acetate=9:1-1:1) to give1-(2,3,4,6-tetra-O-acetyl-β-D-glucopyranosyl)-3-(5-(3-difluoromethylphenyl)-2-thienylmethyl)-4-methylbenzene(82 mg). APCI-Mass m/Z 662 (M+NH₄).

(3) The above obtained1-(2,3,4,6-tetra-O-acetyl-β-D-glucopyranosyl)-3-(5-(3-difluoromethylphenyl)-2-thienylmethyl)-4-methylbenzene was used and treated in a manner similar toExample 120-(3) to give the desired1-(β-D-glucopyranosyl)-3-(5-(3-difluoromethylphenyl)-2-thienylmethyl)-4-methylbenzeneas colorless powder. APCI-Mass m/Z 494 (M+NH₄).

Example 1311-(β-D-glucopyranosyl)-4-chloro-3-(6-phenyl-3-pyridylmethyl)benzene

5-Bromo-2-chloro-1-(6-phenyl-3-pyridylmethyl)benzene was used andtreated in a manner similar to Example 1 to give the target compound.APCI-Mass m/Z 442/444 (M+H).

In a manner similar to the method disclosed in any of the aboveExamples, the compounds shown in Table 4 below were prepared fromcorresponding starting materials. The numbers shown in a column of“preparation method” in the Table indicates the Example number,according to which the preparation was carried out in the similarmanner.

TABLE 4

Preparation APCI-Mass Examples Ring A R^(4a) Method (m/Z) 132

1 512 (M + NH₄) 133

1 512 (M + NH₄) 134

4 472 (M + NH₄) 135

4 458 (M + NH₄) 136

4 486 (M + NH₄) 137

Cl 1 456/458 (M + NH₄) 138

2 458 (M + NH₄) 139

2 498 (M + NH₄) 140

1 472 (M + NH₄) 141

1 428 (M + H) 142

4 488/490 (M + NH₄) 143

1 428 (M + H) 144

1 474 (M + NH₄) 145

1 488 (M + NH₄) 146

1 463 (M + NH₄) 147

CF₃ 1 436 (M + NH₄) 148

1 468 (M + NH₄) 149

1 462 (M + NH₄) 150

103 484 (M + H) 151

124 469 (M + NH₄) 152

122 498/500 (M + H) 153

128 454/456 (M + H) 154

2 470/472 (M + NH₄) 155

122 489/491 (M + NH₄) 156

122 466/468 (M + H)

Example 1571-(β-D-glucopyranosyl)-4-chloro-3-(6-isopropyloxybenzo[b]thiophen-2-ylmethyl)benzene

5-Bromo-2-chloro-1-(6-isopropyloxybenzo[b]thiophen-2-yl-methyl)benzenewas treated in a manner similar to Example 1 to give the targetcompound. APCI-Mass m/Z 496/498 (M+NH₄).

Example 158 1-(β-D-glucopyranosyl)-4-methyl-3-(2-thienylmethyl)benzene

(1)1-(2,3,4,6-tetra-O-acetyl-β-D-glucopyranosyl)-3-(5-chloro-2-thienylmethyl)-4-methylbenzene57 (12.0 g) obtained in Example 120-(1) was dissolved in tetrahydrofuran(120 ml) and methanol (360 ml), and added thereto were triethylamine(24.2 ml) and 10% palladium carbon catalyst (wet, 3.6 g), and themixture was stirred at room temperature for 18 hours under hydrogenatmosphere under normal pressure. The insoluble materials were filteredoff, washed with tetrahydrofuran, and the filtrate was evaporated underreduced pressure. The residue was dissolved in chloroform, washedsuccessively with a 5% aqueous citric acid solution, a saturated aqueoussodium hydrogen carbonate solution and water, and dried over sodiumsulfate. The solvent was evaporated under reduced pressure, and theresidue was recrystallized from ethanol to give1-(2,3,4,6-tetra-O-acetyl-β-D-glucopyranosyl)-4-methyl-3(2-thienylmethyl)benzene(7.79 g) as colorless crystals. APCI-Mass m/Z 536 (M+NH₄).

(2) The above1-(2,3,4,6-tetra-O-acetyl-β-Dglucopyranosyl)-4-methyl3-(2-thienylmethyl)benzenewas treated in a manner similar to Example 106-(3) to give the desired1-(β-D-glucopyranosyl)-4-methyl-3-(2-thienylmethyl)benzene as colorlesspowder. APCI-Mass m/Z 368 (M+NH₄).

Example 1591-(β-D-glucopyranosyl)-3-(5-bromo-2-thienylmethyl)-4-methylbenzene

(1)1-(2,3,4,6-tetra-O-acetyl-β-D-glucopyranosyl)-4-methyl3-(2-thienylmethyl)benzene(11.08 g) obtained in Example 158-(1) was dissolved in chloroform (100ml), and added dropwise thereto at 0° C. was a solution of bromine (3.71g) in chloroform (13 ml). The mixture was stirred at 0° C. for 1.5hours, and then, at room temperature for 1 hour, and the mixture waspoured into a 10% aqueous sodium thiosulfate solution and a saturatedaqueous sodium hydrogen carbonate solution. The mixture was extractedtwice with chloroform, washed with brine, and dried over magnesiumsulfate. The solvent was evaporated under reduced pressure, and theresidue was purified by silica gel column chromatography (hexane:ethylacetate=80:20-67:33) to give1-(2,3,4,6-tetra-O-acetyl-β-D-glucopyranosyl)-3-(5-bromo-2-thienylmethyl)-4-methylbenzene(7.13 g) as a colorless solid. APCI-Mass m/Z 614/616 (M+NH₄).

(2) The above1-(2,3,4,6-tetra-O-acetyl-β-Dglucopyranosyl)-3-(5-bromo-2-thienylmethyl)-4-methylbenzenewas treated in a manner similar to Example 106-(3) to give the desired1-(β-D-glucopyranosyl)-3-(5-bromo-2-thienylmethyl)-4-methylbenzene ascolorless powder. APCI-Mass m/Z 446/448 (M+NH₄).

Example 160 1-(β-D-glucopyranosyl)-3-(5-phenyl-2-thienylmethyl)benzene

2-Phenylthiophene and 3-bromobenzadlehyde was treated in a mannersimilar to Example 4 to give the target compound. APCI-Mass m/Z 430(M+NH₄).

Example 1611-(β-D-glucopyranosyl)-3-(5-cyano-2-thienylmethyl)-4-methylbenzene

(1)1-(2,3,4,6-tetra-O-acetyl-β-D-glucopyranosyl)-3-(5-bromo-2-thienylmethyl)-4-methylbenzene(500 mg) obtained in Example 159-(1) was dissolved inN,N-dimethylacetamide (10 ml), and added thereto were zinc cyanide (98mg), tris(dibenzylideneacetone)dipalladium(0) (77 mg),1,1′-bis(diphenylphosphino)ferrocene (47 mg) and zinc power (14 mg). Themixture was heated under stirring at 120° C. overnight. The reactionsolution was cooled, diluted with ethyl acetate and water, and theinsoluble materials were filtered off. The organic layer of the filtratewas washed twice with water and successively washed with brine. Afterdrying the same over sodium sulfate, the solvent was evaporated underreduced pressure, and the residue was purified by silica gel columnchromatography (hexane:ethyl acetate=100:0-50:50) to give1-(2,3,4,6-tetra-O-acetyl-β-Dglucopyranosyl)-3-(5-cyano-2-thienylmethyl)-4-methylbenzene(207 mg) as colorless crystals. APCI-Mass m/Z 561 (M+NH₄).

(2) The above1-(2,3,4,6-tetra-O-acetyl-β-Dglucopyranosyl)-3-(5-cyano-2-thienylmethyl)-4-methylbenzenewas treated in a manner similar to Example 106-(3) to give the desired1-(β-D-glucopyranosyl)-3-(5-cyano-2-thienylmethyl)-4-methylbenzene ascolorless powder. APCI-Mass m/Z 393 (M+NH₄).

Example 1621-(β-D-glucopyranosyl)-4-fluoro-3-(5-(2pyridyl)-2-thienylmethyl)naphthalene

4-Bromo-1-fluoro-2-(5-(2-pyridyl)-2-thienylmethyl)naphthalene wastreated in a manner similar to Example 1 to give the target compound.APCI-Mass m/Z 482 (M+H).

Example 1631-(β-D-glucopyranosyl)-3-(5-bromo-2-thienylmethyl)-4-chlorobenzene

1-(2,3,4,6-tetra-O-acetyl-β-D-glucopyranosyl)-3-(5-bromo-2-thienylmethyl)-4-chlorobenzene71 obtained in Example 128-(4) was treated in a manner similar toExample 106-(3) to give the target compound. APCI-Mass m/Z 466/468(M+NH₄).

Example 1641-(β-D-glucopyranosyl)-4-methyl-3-(5-(2-pyrimidinyl)-2-thienylmethyl)benzene

1-(2,3,4,6-tetra-O-acetyl-β-D-glucopyranosyl)-3-(5-bromo-2-thienylmethyl)-4-methylbenzeneobtained in Example 159-(1) and tri-n-butyl(2-pyrimidinyl)tin 54 weretreated in a manner similar to Example 128-(5) and (6) to give thetarget compound. APCI-Mass m/Z 429 (M+H).

Example 1651-(β-D-glucopyranosyl)-4-methyl-3-(5-(2-thiazolyl)-2-thienylmethyl)benzene

1-(2,3,4,6-tetra-O-acetyl-β-D-glucopyranosyl)-3-(5-bromo-2-thienylmethyl)-4-methylbenzeneobtained in Example 159-(1) and tri-n-butyl(2-thiazolyl)tin were treatedin a manner similar to Example 128-(5) and (6) to give the targetcompound. APCI-Mass m/Z 434 (M+H).

Example 1661-(β-D-glucopyranosyl)-4-chloro-3-(6-ethyl-3-pyridylmethyl)benzene

5-Bromo-2-chloro-1-(6-ethyl-3-pyridylmethyl)benzene was treated in amanner similar to Example 1 to give the target compound. APCI-Mass m/Z394/396 (M+H).

Example 1671-(β-D-glucopyranosyl)-4-chloro-3-(6-ethylbenzo[b]thiophen-2-ylmethyl)benzene

6-Ethylbenzo[b]thiophene and 5-bromo-2-chlorobenzaldehyde obtained inReference Example 16-(1) were treated in a manner similar to Example 4to give the target compound. APCI-Mass m/Z 466/468 (M+H).

Example 1681-(β-D-glucopyranosyl)-4-chloro-3-(5-(6-fluoro3-pyridyl)-2-thienylmethyl)benzene

(1)1-(2,3,4,6-tetra-O-acetyl-β-D-glucopyranosyl)-3-(5bromo-2-thienylmethyl)-4-chlorobenzene71 (500 mg) obtained in Example 128-(4) was dissolved in1,2-dimethoxyethane (15 ml), and added thereto were6-fluoropyridine-3-boronic acid 58 (228 mg),tetrakis(triphenylphosphine)palladium(0) (94 mg) and cesium fluoride(738 mg). The mixture was heated under reflux for 30 minutes. Thereaction solution was poured into a saturated aqueous sodium hydrogencarbonate solution and the mixture was extracted with ethyl acetate. Theextract was washed with brine and dried over magnesium sulfate, and thesolvent was evaporated under reduced pressure. The residue was purifiedby silica gel column chromatography (hexane:ethyl acetate=75:25-60:40)to give1-(2,3,4,6-tetra-O-acetyl-β-D-glucopyranosyl)-4-chloro-3-(5-(6-fluoro-3-pyridyl)-2-thienylmethyl)benzene(454 mg) as a colorless solid. APCI-Mass m/Z 634/636 (M+H).

(2) The above1-(2,3,4,6-tetra-O-acetyl-β-Dglucopyranosyl)-4-chloro-3-(5-(6-fluoro-3-pyridyl)-2-thienylmethyl)benzenewas treated in a manner similar to Example 106-(3) to give the desired1-(β-D-glucopyranosyl)-4-chloro-3-(5-(6-fluoro-3-pyridyl)-2-thienylmethyl)benzeneas colorless powder. APCI-Mass m/Z 483 (M+NH₄), 466 (M+H).

Example 1691-(β-D-glucopyranosyl)-4-chloro-3-(5-(6-methoxy-3-pyridyl)-2-thienylmethyl)benzene

1-(2,3,4,6-tetra-O-acetyl-β-D-glucopyranosyl)-3-(5-bromo-2-thienylmethyl)-4-chlorobenzene71 obtained in Example 128-(4) and 6-methoxypyridine-3-boronic acid weretreated in a manner similar to Example 168 to give the target compound.APCI-Mass m/Z 478/480 (M+H).

Example 1701-(β-D-glucopyranosyl)-4-chloro-3-(5-(6-methoxy-2-pyridyl)-2-thienylmethyl)benzene

1-(2,3,4,6-tetra-O-acetyl-β-D-glucopyranosyl)-3-(5-bromo-2-thienylmethyl)-4-chlorobenzene71 obtained in Example 128-(4) and tri-n-butyl(6-methoxy-2-pyridyl)tin(see Gros, Philippe; Fort, Yves. Synthesis (1999), 754-756) were treatedin a manner similar to Example 128-(5) and (6) to give the targetcompound. APCI-Mass m/Z 478/480 (M+H).

Example 1711-(β-D-glucopyranosyl)-4-chloro-3-(1-oxo-2-isoindolinylmethyl)benzene

5-Bromo-2-chloro-1-(1-oxo-2-isoindolynilmethyl)benzene was treated in amanner similar to Example 2 to give the target compound. APCI-Mass m/Z437/439 (M+NH₄).

Example 1721-(β-D-glucopyranosyl)-4-chloro-3-(1-phenyl-4-pyrazolylmethyl)benzene

5-Bromo-2-chloro-1-(1-phenyl-4-pyrazolylmethyl)benzene was treated in amanner similar to Example 1 to give the target compound. APCI-Mass m/Z431/433 (M+H).

Example 1731-(β-D-glucopyranosyl)-4-chloro-3-(5-(6-ethoxy-2-pyridyl)-2-thienylmethyl)benzene

(1)1-(2,3,4,6-tetra-O-acetyl-β-D-glucopyranosyl)-3-(5bromo-2-thienylmethyl)-4-chlorobenzene71 obtained in Example 128-(4) and tri-n-butyl(6-ethoxy-2-pyridyl)tin(see WO 00/74681) were treated in a manner similar to Example 128-(5) togive1-(2,3,4,6-tetra-O-acetyl-β-Dglucopyranosyl)-4-chloro-3-(5-(6-ethoxy-2-pyridyl)-2-thienylmethyl)benzeneas colorless crystals. APCI-Mass m/Z 660/662 (M+H).

(2) The above1-(2,3,4,6-tetra-O-acetyl-β-Dglucopyranosyl)-4-chloro-3-(5-(6-ethoxy-2-pyridyl)-2-thienylmethyl)benzene(245 mg) was dissolved in tetrahydrofuran (5 ml), added thereto was asolution of sodium hydride (oil, 9 mg) in ethanol (5 ml), and themixture was stirred at room temperature for 2 hours. The solvent wasevaporated under reduced pressure and the residue was purified by silicagel column chromatography (chloroform:methanol=100:0-90:10) to give thedesired1-(β-D-glucopyranosyl)-4-chloro3-(5-(6-ethoxy-2-pyridyl)-2-thienylmethyl)benzene(145 mg) as colorless powder. APCI-Mass m/Z 492/494 (M+H).

Example 1741-(β-D-glucopyranosyl)-4-chloro-3-(6-n-propyloxybenzo[b]thiophen-2-ylmethyl)benzene

5-Bromo-2-chloro-1-(6-n-propyloxybenzo[b]thiophen-2-yl methyl)benzenewas treated in a manner similar to Example 1 to give the targetcompound. APCI-Mass m/Z 496/498 (M+NH₄).

Example 1751-(β-D-glucopyranosyl)-4-chloro-3-(6-(2-fluoroethyloxy)benzo[b]thiophen-2-ylmethyl)benzene

5-Bromo-2-chloro-1-(6-(2-fluoroethyloxy)benzo[b]thiophen-2-ylmethyl)benzenewas treated in a manner similar to Example 1 to give the targetcompound. APCI-Mass m/Z 500/502 (M+NH₄).

Example 1761-(β-D-glucopyranosyl)-3-(5-(4-difluoromethylphenyl)-2-thienylmethyl)-4-methylbenzene

(1)1-(2,3,4,6-tetra-O-acetyl-β-D-glucopyranosyl)-3-(5bromo-2-thienylmethyl)-4-methylbenzenefrom Example 159-(1) and 4-formylphenylboronic acid were treated in amanner similar to Example 168-(1) to give1-(2,3,4,6-tetra-O-acetyl-β-D-glucopyranosyl)-3-(5-(4-formylphenyl)-2-thienylmethyl)-4-methylbenzeneas a colorless solid. APCI-Mass m/Z 640 (M+NH₄).

(2) The above1-(2,3,4,6-tetra-O-acetyl-β-Dglucopyranosyl)-3-(5-(4-formylphenyl)-2-thienylmethyl)-4-methylbenzenewas treated in a manner similar to Example 130-(2) to give the desired1-(2,3,4,6-tetra-O-acetyl-β-Dglucopyranosyl)-3-(5-(4-difluoromethylphenyl)-2-thienylmethyl)-4-methylbenzeneas colorless crystals. APCI-Mass m/Z 662 (M+NH₄).

(3) The above1-(2,3,4,6-tetra-O-acetyl-β-Dglucopyranosyl)-3-(5-(4-difluoromethylphenyl)-2-thienylmethyl)-4-methylbenzenewas treated in a manner similar to Example 106-(3) to give the desired1-(β-D-glucopyranosyl)-3-(5-(4-difluoromethylphenyl)-2-thienylmethyl)-4-methylbenzeneas colorless powder. APCI-Mass m/Z 494 (M+NH₄).

Example 1771-(β-D-glucopyranosyl)-3-(5-(3,4-difluorophenyl)-2-thienylmethyl)-4-methylbenzene

(1)1-(2,3,4,6-tetra-O-acetyl-β-D-glucopyranosyl)-3-(5bromo-2-thienylmethyl)-4-methylbenzeneobtained in Example 159-(1) and 3,4-difluorophenylboronic acid weretreated in a manner similar to Example 168-(1) to give1-(2,3,4,6-tetra-Oacetyl-β-D-glucopyranosyl)-3-(5-(3,4-difluorophenyl)-2-thienylmethyl)-4-methylbenzeneas colorless crystals. APCI-Mass m/Z 648 (M+NH₄).

(2) The above1-(2,3,4,6-tetra-O-acetyl-β-Dglucopyranosyl)-3-(5-(3,4-difluorophenyl)-2-thienylmethyl)-4-methylbenzenewas treated in a manner similar to Example 106-(3) to give the desired1-(β-D-glucopyranosyl)-3(5-(3,4-difluorophenyl)-2-thienylmethyl)-4-methylbenzeneas colorless powder. APCI-Mass m/Z 480 (M+NH₄).

Example 1781-(β-D-glucopyranosyl)-4-chloro-3-(5-(3-difluoromethylphenyl)-2-thienylmethyl)benzene

(1)1-(2,3,4,6-tetra-O-acetyl-β-D-glucopyranosyl)-3-(5bromo-2-thienylmethyl)-4-chlorobenzene71 obtained in Example 128-(4) and 3-formylphenylboronic acid weretreated in a manner similar to Example 168-(1) to give1-(2,3,4,6-tetra-O-acetyl-β-D-glucopyranosyl)-4-chloro-3-(5-(3-formylphenyl)-2-thienylmethyl)benzeneas a colorless solid. APCI-Mass m/Z 660/662 (M+NH₄).

(2) The above1-(2,3,4,6-tetra-O-acetyl-β-Dglucopyranosyl)-4-chloro-3-(5-(3-formylphenyl)-2-thienylmethyl)benzenewas treated in a manner similar to Example 130-(2) to give1-(2,3,4,6-tetra-O-acetyl-β-Dglucopyranosyl)-4-chloro-3-(5-(3-difluoromethylphenyl)-2-thienylmethyl)benzeneas colorless crystals. APCI-Mass m/Z 682/684 (M+NH₄).

(3) The above1-(2,3,4,6-tetra-O-acetyl-β-Dglucopyranosyl)-4-chloro-3-(5-(3-difluoromethylphenyl)-2-thienylmethyl)benzenewas treated in a manner similar to Example 120-(3) to give the desired1-(β-D-glucopyranosyl)-4-chloro-3-(5-(3-difluoromethylphenyl)-2-thienylmethyl)benzeneas colorless powder. APCI-Mass m/Z 514/516 (M+NH₄).

Example 1791-(β-D-glucopyranosyl)-4-chloro-3-(5-(4-difluoromethylphenyl)-2-thienylmethyl)benzene

(1)1-(2,3,4,6-tetra-O-acetyl-β-D-glucopyranosyl)-3-(5bromo-2-thienylmethyl)-4-chlorobenzene71 obtained in Example 128-(4) and 4-formylphenylboronic acid weretreated in a manner similar to Example 168-(1) to give1-(2,3,4,6-tetra-Oacetyl-β-D-glucopyranosyl)-4-chloro-3-(5-(4-formylphenyl)-2-thienylmethyl)benzeneas a colorless solid. APCI-Mass m/Z 660/662 (M+NH₄).

(2) The above1-(2,3,4,6-tetra-O-acetyl-β-Dglucopyranosyl)-4-chloro-3-(5-(4-formylphenyl)-2-thienylmethyl)benzenewas treated in a manner similar to Example 130-(2) to give1-(2,3,4,6-tetra-O-acetylβ-D-glucopyranosyl)-4-chloro-3-(5-(4-difluoromethylphenyl)-2-thienylmethyl)benzeneas colorless crystals. APCI-Mass m/Z 682/684 (M+NH₄).

(3) The above1-(2,3,4,6-tetra-O-acetyl-β-Dglucopyranosyl)-4-chloro-3-(5-(4-difluoromethylphenyl)-2-thienylmethyl)benzenewas treated in a manner similar to Example 120-(3) to give the desired1-(β-D-glucopyranosyl)-4-chloro-3-(5-(4-difluoromethylphenyl)-2-thienylmethyl)benzeneas colorless powder. APCI-Mass m/Z 514/516 (M+NH₄).

Example 1801-(β-D-glucopyranosyl)-4-chloro-3-(5-(4-difluoromethyl-3-fluorophenyl)-2-thienylmethyl)benzene

(1)1-(2,3,4,6-Tetra-O-acetyl-β-D-glucopyranosyl)-3-(5bromo-2-thienylmethyl)-4-chlorobenzeneobtained in Example 128-(4) and 3-fluoro-4-formylphenylboronic acid weretreated in a manner similar to Example 168-(1) to give1-(2,3,4,6-tetra-O-acetyl-β-D-glucopyranosyl)-4-chloro3-(5-(3-fluoro-4-formylphenyl)-2-thienylmethyl)benzeneas colorless foam. APCI-Mass m/Z 678/680 (M+NH₄).

(2)1-(2,3,4,6-Tetra-O-acetyl-β-D-glucopyranosyl)-4-chloro-3-(5-(3-fluoro-4-formylphenyl)-2-thienylmethyl)benzenewas treated in a manner similar to Example 178-(2) and (3) to give thedesired1-(β-D-glucopyranosyl)-4-chloro3-(5-(4-difluoromethyl-3-fluorophenyl)-2-thienylmethyl)benzeneas a colorless foam. APCI-Mass m/Z 532/534 (M+NH₄).

Example 1811-(β-D-glucopyranosyl)-4-chloro-3-(5-(1H-tetrazol-5-yl)-2-thienylmethyl)benzene

(1)1-(2,3,4,6-tetra-O-acetyl-β-D-glucopyranosyl)-3-(5bromo-2-thienylmethyl)-4-chlorobenzeneobtained in Example 128-(4) and(2-benzyloxymethyl-2H-tetrazol-5-yl)trin-butyltin (see Tetrahedron Lett.(2000) 2805) were treated in a manner similar to Example 128-(5) to give1-(2,3,4,6-tetra-O-acetyl-β-D-glucopyranosyl)-3-(5-(2-benzyloxymethyl-2H-tetrazol-5-yl)-2-thienylmethyl)-4-chlorobenzeneas colorless solid. APCI-Mass m/Z 727/729 (M+H).

(2) A mixture of1-(2,3,4,6-tetra-O-acetyl-β-D-glucopyranosyl)-3-(5-(2-benzyloxymethyl-2H-tetrazol-5-yl)-2-thienylmethyl)-4-chlorobenzene(247 mg), 6M aqueous hydrochloric acid solution (2 ml) and methanol (20ml) was refluxed overnight. The solvent was evaporated under reducedpressure and the residue was triturated with diethyl ether to give thedesired1-(β-D-glucopyranosyl)-4-chloro-3-(5-(1H-tetrazol-5-yl)-2-thienylmethyl)benzene(172 mg) as colorless powder. ESI-Mass m/Z 437/439 (M−H).

Example 1821-(β-D-glucopyranosyl)-4-chloro-3-(5-(2-methyl-2H-tetrazol-5-yl)-2-thienylmethyl)benzene

1-(β-D-glucopyranosyl)-4-chloro-3-(5-(1H-tetrazol-5-yl)-2-thienylmethyl)benzene(140 mg) obtained in Example 181 was dissolved in dimethylformamide (5ml) and added thereto were methyl iodide (100 μl) and potassiumcarbonate (220 mg). The mixture was stirred at room temperatureovernight. The reaction solution was poured into water and the mixturewas extracted with ethyl acetate. The extract was washed with brine anddried over sodium sulfate, and the solvent was evaporated under reducedpressure to give the desired1-(β-D-glucopyranosyl)-4-chloro-3-(5-(2-methyl-2H-tetrazol-5-yl)-2-thienylmethyl)benzeneas colorless powder. APCI-Mass m/Z 470/472 (M+NH₄).

Example 1831-(β-D-glucopyranosyl)-4-chloro-3-(5-(4-cyano-3-fluorophenyl)-2-thienylmethyl)benzene

(1)1-(2,3,4,6-Tetra-O-acetyl-β-D-glucopyranosyl)-4-chloro-3-(5-(3-fluoro-4-formylphenyl)-2-thienylmethyl)benzene(272 mg) obtained in Example 180-(1) was dissolved inN-methyl-2-pyrrolidone (10 ml) and added thereto was hydroxylaminehydrochloride (34 mg). The mixture was heated under stirring at 117° C.overnight. The reaction solution was cooled and diluted with ethylacetate and water. The organic layer was washed with water andsuccessively washed with brine. After drying over magnesium sulfate, thesolvent was evaporated under reduced pressure. The residue was purifiedby silica gel column chromatography (hexane:ethyl acetate=3:1-2:1) togive1-(2,3,4,6-tetra-O-acetyl-β-D-glucopyranosyl)-4-chloro-3(5-(4-hydroxyimino-3-fluorophenyl)-2-thienylmethyl)benzene(177 mg) as colorless caramel. APCI-Mass m/Z 693/695 (M+NH₄).

(2) The above1-(2,3,4,6-tetra-O-acetyl-β-D-glucopyranosyl)-4-chloro-3-(5-(4-hydroxyimino-3-fluorophenyl)-2-thienylmethyl)benzene(175 mg) was dissolved in chloroform (5 ml) and added thereto was1,1′-carbonyldiimidazole (46 mg). The mixture was stirred at roomtemperature overnight. 1,1′-Carbonyldiimidazole (92 mg) was furtheradded thereto, and the mixture was stirred at 40° C. for 6 hours. Thereaction solution was cooled and diluted with ethyl acetate and water.The organic layer was separated and successively washed with brine.After drying over magnesium sulfate, the solvent was evaporated underreduced pressure. The residue was purified by silica gel columnchromatography (hexane:ethyl acetate=2:1) to give1-(2,3,4,6-tetra-O-acetyl-β-D-glucopyranosyl)-4-chloro-3(5-(4-cyano-3-fluorophenyl)-2-thienylmethyl)benzene(158 mg) as colorless caramel. APCI-Mass m/Z 675/677 (M+NH₄).

(3) The above1-(2,3,4,6-tetra-O-acetyl-β-D-glucopyranosyl)-4-chloro-3-(5-(4-cyano-3-fluorophenyl)-2-thienylmethyl)-benzenewas treated in a manner similar to Example 106-(3) to give desired1-(β-D-glucopyranosyl)-4-chloro-3-(5-(4-cyano-3-fluorophenyl)-2-thienylmethyl)benzeneas pale yellow powder. APCI-Mass m/Z 507/509 (M+NH₄).

Example 1841-(β-D-glucopyranosyl)-4-chloro-3-(1,3-dihydro-isoindol-2-ylmethyl)benzene

(In the above scheme, OTBDPS is a tert-butyldiphenylsilyloxy group, andthe other symbols are the same as defined above.)

(1) A mixed solution of5-bromo-2-chloro-1-(tert-butyl-diphenylsilyloxymethyl)benzene 77 (10.83g) and 2,3,4,6-tetrakis-O-trimethylsilyl-D-glucono-1,5-lactone 2 (seeU.S. Pat. No. 6,515,117) (13.2 g) in tetrahydrofuran (400 ml) was cooledto −78° C. under argon atmosphere, and thereto was added dropwisetert-butyl lithium (1.60 M pentane solution, 30.9 ml), and the mixturewas stirred at the same temperature for 30 minutes to give a compound78. Without isolating this compound, a solution of methanesulfonic acid(6.12 ml) in methanol (200 ml) was added to the reaction solution, andthe reaction mixture was warmed to room temperature, and stirred at thesame temperature for 15 hours. Under ice-cooling, to the mixture wasadded a saturated aqueous sodium hydrogen carbonate solution, and themixture was extracted with ethyl acetate. The extract was washed withbrine, and dried over magnesium sulfate. The solvent was evaporatedunder reduced pressure, and the residue was purified by silica gelcolumn chromatography (chloroform:methanol=93:7) to give a methyl ethercompound 79 (9.71 g) as colorless powder. APCI-Mass m/Z 590/592 (M+NH₄).

(2) A solution of the above methyl ether compound 79 (3.46 g) indichloromethane (70 ml) was cooled to 0° C. under argon atmosphere, andthereto were added dropwise successively triethylsilane (2.89 ml) andboron trifluoride.diethyl ether complex (2.28 ml). The mixture wasstirred at the same temperature for 1 hour. Under ice-cooling, asaturated aqueous sodium hydrogen carbonate solution was added, and themixture was extracted with ethyl acetate. The extract was washed withbrine and dried over magnesium sulfate, and the solvent was evaporatedunder reduced pressure. The residue was purified by silica gel columnchromatography (chloroform:methanol=100:0-94:4) to give1-(β-D-glucopyranosyl)-4-chloro-3-(tert-butyldiphenylsilyloxymethyl)benzene80 (2.52 g) as colorless powder. APCI-Mass m/Z 560/562 (M+NH₄).

(3) The above compound 80 (4.12 g) was treated in a manner similar toExample 106-(1) to give the compound 81 (5.44 g). APCI-Mass m/Z 728/730(M+NH₄).

(4) A mixed solution of the above compound 81 (5.44 g), acetic acid(1.29 ml) in tetrahydrofuran (60 ml) was cooled to 0° C. under argonatmosphere, and thereto was added tetrabutyl ammonium fluoride (1.0 Mtetrahydrofuran solution, 8.43 ml). The mixture was stirred at the sametemperature for 30 minutes, and then further stirred at room temperaturefor 15 hours. The mixture was diluted with ethyl acetate and washedsuccessively with 0.4 M aqueous hydrochloric acid solution, a saturatedaqueous sodium hydrogen carbonate solution and brine. The mixture wasdried over magnesium sulfate, and the solvent was evaporated underreduced pressure. The residue was purified by silica gel columnchromatography (hexane:ethyl acetate=4:1-1:1) to give the compound 82(2.97 g) as a colorless solid. APCI-Mass m/Z 490/492 (M+NH₄).

(5) A solution of the above compound 82 (1.60 g) in dichloromethane (50ml) was cooled to 0° C. under argon atmosphere, and thereto was addedDess-Martin periodinane (1.58 g). The mixture was warmed to roomtemperature and stirred at the same temperature for 3 hours. The mixturewas diluted with ethyl acetate, and insoluble materials were filteredoff. The filtrate was washed successively with a saturated aqueoussodium hydrogen carbonate solution and brine, and dried over magnesiumsulfate. The solvent was evaporated under reduced pressure, and theresidue was purified by silica gel column chromatography (hexane:ethylacetate=3:1-1:1) to give5-(2,3,4,6-tetra-O-acetyl-β-D-glucopyranosyl)-2-chlorobenzaldehyde 83(1.35 g) as colorless crystals. APCI-Mass m/Z 488/490 (M+NH₄).

(6) To a mixed solution of the above5-(2,3,4,6-tetra-O-acetyl-β-D-glucopyranosyl)-2-chlorobenzaldehyde 83(325 mg), 2,3-dihydro-1H-isoindole (98 mg), acetic acid (82 mg) in1,2-dichloroethane (5 ml) was added sodium triacetoxyborohydride (219mg). The mixture was stirred at room temperature for 3 hours, and cooledto 0° C. A saturated aqueous sodium hydrogen carbonate solution wasadded thereto to basify the reaction mixture. The mixture was extractedwith ethyl acetate, and the extract was washed with brine, and driedover magnesium sulfate. The solvent was evaporated under reducedpressure, and the residue was purified by silica gel columnchromatography (hexane:ethyl acetate=1:0-1:1) to give1-(2,3,4,6-tetra-O-acetyl-β-D-glucopyranosyl)-4-chloro-3-(1,3-dihydro-isoindol-2-ylmethyl)benzene84 (234 mg) as a colorless solid. APCI-Mass m/Z 574/576 (M+H).

(7) The above1-(2,3,4,6-tetra-O-acetyl-β-D-glucopyranosyl)-4-chloro-3-(1,3-dihydro-isoindol-2-ylmethyl)benzene84 was treated in a manner similar to Example 106-(3) to give thedesired1-(β-D-glucopyranosyl)-4-chloro-3-(1,3-dihydro-isoindol-2-ylmethyl)benzene85 as colorless powder. APCI-Mass m/Z 406/408 (M+H).

Example 1851-(β-D-glucopyranosyl)-4-methyl-3-(5-(3-cyano-4-fluorophenyl)-2-thienylmethyl)benzene

1-(2,3,4,6-tetra-O-acetyl-β-D-glucopyranosyl)-3-(5-bromo-2-thienylmethyl)-4-methylbenzeneobtained in Example 159-(1) and 4-fluoro-3-formylphenylboronic acid wereused and treated in a manner similar to Example 177-(1) and Example 183to give the title compound as colorless powder. APCI-Mass m/z 487(M+NH₄).

Example 1861-(β-D-glucopyranosyl)-3-(5-(2-cyano-5-pyridyl)-2-thienylmethyl)-4-methylbenzene

(1)1-(2,3,4,6-Tetra-O-acetyl-β-D-glucopyranosyl)-3-(5bromo-2-thienylmethyl)-4-methylbenzene(597 mg) obtained in Example 159-(1) was dissolved inN-methyl-2-pyrrolidone (10 ml) and added thereto weretri-n-butyl(2-cyano-5-pyridyl)tin (590 mg),dichlorobis(triphenylphosphine)palladium(II) (70 mg) and copper(I)iodide (19 mg). The mixture was heated under stirring at 100° C. for 4hours. The reaction solution was cooled and diluted with ethyl acetateand water. The organic layer was washed with water and successivelywashed with brine. After drying over magnesium sulfate, the solvent wasevaporated under reduced pressure. The residue was purified by silicagel column chromatography (hexane:ethyl acetate=2:1) to give1-(2,3,4,6-tetra-O-acetyl-β-D-glucopyranosyl)-3-(5-(2cyano-5-pyridyl)-2-thienylmethyl)-4-methylbenzene(351 mg) as colorless powder. APCI-Mass m/Z 621 (M+H).

(2) The above1-(2,3,4,6-tetra-O-acetyl-β-D-glucopyranosyl)-3-(5-(2-cyano-5-pyridyl)-2-thienylmethyl)-4-methylbenzene(62 mg) was dissolved in a mixture of tert-butanol (3ml)-tetrahydrofuran (3 ml) and added thereto was sodium tert-butoxide(48 mg). The mixture was stirred at room temperature for 3.5 hours.Sodium tert-butoxide (19 mg) was further added thereto, and the mixturewas stirred at room temperature for 1 hour. To the mixture was added asaturated aqueous ammonium chloride solution at 0° C., and the mixturewas extracted with ethyl acetate twice. The extract was washed withbrine, dried over magnesium sulfate, and the solvent was evaporatedunder reduced pressure. The residue was purified by silica gel columnchromatography (chloroform:methanol=19:1) to give the desired1-(β-D-glucopyranosyl)-3-(5-(2cyano-5-pyridyl)-2-thienylmethyl)-4-methylbenzene(23 mg) as colorless powder. APCI-Mass m/Z 470 (M+NH₄).

Example 1871-(β-D-glucopyranosyl)-4-chloro-3-(5-(2-cyano-5-pyridyl)-2-thienylmethyl)benzene

(1)1-(2,3,4,6-Tetra-O-acetyl-β-D-glucopyranosyl)-3-(5bromo-2-thienylmethyl)-4-chlorobenzeneobtained in Example 128-(4) was treated in a manner similar to Example186-(1) to give1-(2,3,4,6-tetra-O-acetyl-β-D-glucopyranosyl)-4-chloro-3-(5-(2-cyano-5-pyridyl)-2-thienylmethyl)benzeneas colorless powder. APCI-Mass m/Z 641/643 (M+H).

(2)1-(2,3,4,6-Tetra-O-acetyl-β-D-glucopyranosyl)-4-chloro-3-(5-(2-cyano-5-pyridyl)-2-thienylmethyl)benzenewas treated in a manner similar to Example 186-(2) to give the desired1-(β-D-glucopyranosyl)-4-chloro-3-(5-(2cyano-5-pyridyl)-2-thienylmethyl)benzeneas pale yellow powder. APCI-Mass m/Z 490/492 (M+NH₄).

Example 1881-(β-D-glucopyranosyl)-3-(5-(2-carbamoyl-5-pyridyl)-2-thienylmethyl)-4-chlorobenzene

(1)1-(2,3,4,6-Tetra-O-acetyl-β-D-glucopyranosyl)-4-chloro-3-(5-(2-cyano-5-pyridyl)-2-thienylmethyl)benzeneobtained in Example 187-(1) was treated in a manner similar to Example106-(3) to give the mixture of1-(β-D-glucopyranosyl)-4-chloro-3-(5-(2-cyano-5-pyridyl)-2-thienylmethyl)benzeneand1-(β-D-glucopyranosyl)-4-chloro-3-(5-(2-methoxyimidoyl-5-pyridyl)-2-thienylmethyl)benzene.This mixture was dissolved in methanol, and sodium methoxide (28%methanol solution, 1 drop) was added thereto, and the mixture wasstirred at 60° C. for 6 hours. The reaction solution was cooled and thesolvent was evaporated under reduced pressure to give pure1-(β-D-glucopyranosyl)-4-chloro-3-(5-(2-methoxyimidoyl-5-pyridyl)-2-thienylmethyl)benzene.APCI-Mass m/Z 505/507 (M+H).

(2) The above1-(β-D-glucopyranosyl)-4-chloro-3-(5-(2-methoxyimidoyl-5-pyridyl)-2-thienylmethyl)benzenewas suspended in tetrahydrofuran, and sodium hydride (60% mineral oilsuspension, 2 equivalent) was added thereto, and the mixture was stirredunder reflux for 3 hours. The reaction solution was cooled and to themixture was added a saturated aqueous ammonium chloride solution at 0°C., and the mixture was extracted with a mixture of ethyl acetate andtetrahydrofuran. The extract was washed with brine, dried over magnesiumsulfate, and the solvent was evaporated under reduced pressure. Theresidue was purified by silica gel column chromatography(chloroform:methanol=9:1-5:1) to give the desired1-(β-D-glucopyranosyl)-3-(5-(2-carbamoyl-5-pyridyl)-2-thienylmethyl)-4-chlorobenzeneas pale yellow powder. APCI-Mass m/Z 491/493 (M+H).

Example 1891-(β-D-glucopyranosyl)-4-fluoro-3-(5-(3-cyanophenyl)-2-thienylmethyl)benzene

(1) 5-bromo-2-fluorobenzaldehyde and 2-chlorothiophene were used andtreated in a manner similar to Example 4 and Example 106-(1) to give1-(2,3,4,6-tetra-O-acetyl-β-D-glucopyranosyl)-3-(5-chloro-2-thienylmethyl)-4-fluorobenzeneas colorless crystals. APCI-Mass m/z 574/576 (M+NH₄). mp 130-131° C.

(2) The above compound was treated in a manner similar to Example158-(1) to give1-(2,3,4,6-tetra-O-acetyl-β-D-glucopyranosyl)-3-(2-thienylmethyl)-4-fluorobenzeneas colorless crystals. APCI-Mass m/z 540 (M+NH₄). mp 119-121° C.

(3) The above compound was treated in a manner similar to Example159-(1) to give1-(2,3,4,6-tetra-O-acetyl-β-D-glucopyranosyl)-3-(5-bromo-2-thienylmethyl)-4-fluorobenzeneas colorless crystals. APCI-Mass m/z 618/620 (M+NH₄). mp 127-129° C.

(4) The above compound and 3-cyanophenylboronic acid were used andtreated in a manner similar to Example 168 to give the title compound ascolorless powder. APCI-Mass m/z 473 (M+NH₄).

Example 1901-(β-D-glucopyranosyl)-4-fluoro-3-(5-(2-thiazolyl)-2-thienylmethyl)benzene

1-(2,3,4,6-tetra-O-acetyl-β-D-glucopyranosyl)-3-(5-bromo-2-thienylmethyl)-4-fluorobenzeneobtained in Example 189-(3) and tri-n-butyl(2-thiazolyl)tin were usedand treated in a manner similar to Example 128 to give the titlecompound as colorless crystals. APCI-Mass m/z 438 (M+NH₄). mp 161.5-162°C.

Example 1911-(β-D-glucopyranosyl)-4-chloro-3-(5-(4-ethoxycarbonylphenyl)-2-thienylmethyl)benzene

(1)1-(2,3,4,6-Tetra-O-acetyl-β-D-glucopyranosyl)-3-(5-bromo-2-thienylmethyl)-4-chlorobenzeneobtained in Example 128-(4) and 4-cyanophenylboronic acid were treatedin a manner similar to Example 168-(1) to give1-(2,3,4,6-tetra-O-acetyl-β-D-glucopyranosyl)-4-chloro-3-(5-(4-cyanophenyl)-2-thienylmethyl)benzeneas colorless powder. APCI-Mass m/Z 657/659 (M+NH₄).

(2) The above1-(2,3,4,6-tetra-O-acetyl-β-D-glucopyranosyl)-4-chloro-3-(5-(4-cyanophenyl)-2-thienylmethyl)benzene(128 mg) was suspended in ethanol (2 ml) and added thereto was aconcentrated hydrochloric acid aqueous solution (1 ml). The mixture washeated reflux for 8.5 hours. The reaction solution was cooled anddiluted with ethyl acetate and water. The organic layer was washed withwater and successively washed with brine. After drying over magnesiumsulfate, the solvent was evaporated under reduced pressure. The residuewas purified by silica gel column chromatography(chloroform:methanol=9:1) to give the desired1-(β-D-glucopyranosyl)-4-chloro-3-(5-(4-ethoxycarbonylphenyl)-2-thienylmethyl)benzene(39 mg) as pale yellow foam. APCI-Mass m/Z 536/538 (M+NH₄).

Example 1921-(β-D-glucopyranosyl)-3-(5-(4-carboxyphenyl)-2-thienylmethyl)-4-chlorobenzene

1-(2,3,4,6-Tetra-O-acetyl-β-D-glucopyranosyl)-4-chloro-3-(5-(4-cyanophenyl)-2-thienylmethyl)benzene(128 mg) obtained in Example 191-(1) was dissolved in acetic acid (2 ml)and added thereto was a concentrated hydrochloric acid aqueous solution(2 ml). The mixture was refluxed for 6.5 hours. To the mixture was addeda 10% aqueous sodium hydroxide solution at 0° C., and the mixture waswashed with ethyl acetate. The aqueous layer was acidified by addingconcentrated hydrochloric acid, and extracted with a mixture of ethylacetate and tetrahydrofuran. The extract was dried over magnesiumsulfate, and the solvent was evaporated under reduced pressure. Theresidue was purified by washing with a mixture of ethyl acetate anddiethyl ether to give the desired1-(β-D-glucopyranosyl)-3-(5-(4-carboxyphenyl)-2-thienylmethyl)-4-chlorobenzene(49 mg) as pale brown powder. ESI-Mass m/Z 489/491 (M−H).

Example 1931-(β-D-glucopyranosyl)-3-(5-(4-carbamoylphenyl)-2-thienylmethyl)-4-chlorobenzene

1-(2,3,4,6-Tetra-O-acetyl-β-D-glucopyranosyl)-4-chloro-3-(5-(4-cyanophenyl)-2-thienylmethyl)benzene(282 mg) obtained in Example 191-(1) was suspended in ethanol (5 ml) andadded thereto was a 6N aqueous sodium hydroxide solution (0.37 ml). Themixture was stirred at room temperature for 10 minutes. To the mixturewas added a 30% aqueous hydrogen peroxide solution (0.2 ml), and themixture was stirred at room temperature for 1.5 hours and at 45° C. for3 hours. To the mixture was added water (20 ml) and the mixture wascooled. The powder was collected by filtration and washed with diethylether and dried to give the desired1-(β-D-glucopyranosyl)-3-(5-(4-carbamoylphenyl)-2-thienylmethyl)-4-chlorobenzene(176 mg) as colorless powder. APCI-Mass m/Z 507/509 (M+NH₄).

Example 1941-(β-D-glucopyranosyl)-4-chloro-3-(5-(5-fluoropyridin-2-yl)-2-thienylmethyl)benzene

In the above scheme, the symbols are defined as above.

(1) The1-(2,3,4,6-tetra-O-acetyl-β-D-glucopyranosyl)-3-(5-bromo-2-thienylmethyl)-4-chlorobenzene71 (750 mg) obtained in Example 128-(4) was dissolved in a mixture ofmethanol (8 ml)-tetrahydrofuran (8 ml), and sodium methoxide (28%methanol solution, 1 drop) was added thereto, and the mixture wasstirred at room temperature for 2 hours. The solvent was evaporatedunder reduced pressure. The residue was dissolved in dichloromethane (20ml), and thereto were added pyridine (0.69 ml) and4-dimethylaminopyridine (15 mg). The mixture was cooled to 0° C., andthereto was added trimethylsilyl trifluoromethanesulfonate (1.54 ml).The mixture was stirred at room temperature for 3 days. To the mixturewas added water, and the mixture was extracted with diethyl ether. Theextract was washed with successively with water, a saturated aqueousammonium chloride solution and brine, and dried over sodium sulfate. Thesolvent was evaporated under reduced pressure to give the compound 86(900 mg) as colorless oil.

(2) A mixed solution of the above compound 86 (900 mg),triisopropoxyborane (252 mg) in tetrahydrofuran (22 ml) was cooled to−78° C. under argon atmosphere. Thereto was added dropwise tert-butyllithium (1.46 M pentane solution, 0.9 ml), and the mixture was stirredat the same temperature for 1 hour. The mixture was warmed to roomtemperature, and thereto was added pinacol (2.24 g). The mixture wasstirred at the same temperature overnight. The mixture was diluted withethyl acetate, and washed successively with water and brine. The solventwas evaporated under reduced pressure to give the compound 87, which wasused in the subsequent reaction without further purification.

(3) The whole amount of the above compound 87 was dissolved indimethoxyethane (20 ml), and thereto were added 2-bromo-5-fluoropyridine(460 mg), tetrakis(triphenylphosphine)palladium(0) (150 mg) and cesiumfluoride (1.4 g). The mixture was stirred at 80° C. for 3 hours. Themixture was cooled to room temperature, acidified with 2 M aqueoushydrochloric acid solution, and stirred at the same temperatureovernight. Under ice-cooling, the reaction mixture was poured into asaturated aqueous sodium hydrogen carbonate solution and the mixture wasextracted with ethyl acetate. The extract was washed with brine anddried over sodium sulfate, and the solvent was evaporated under reducedpressure. The residue was passed through silica gel columnchromatography (chloroform:methanol=100:0-88:12) to give crude oil,which was dissolved in dichloromethane (20 ml). To the mixture wereadded acetic anhydride (0.71 ml), pyridine (0.61 ml), and4-dimethylaminopyridine (13 mg), and the mixture was stirred at roomtemperature for 1 hour. Then, dichloromethane was evaporated underreduced pressure, and the residue was dissolved in ethyl acetate. Themixture was washed successively with 2 M aqueous hydrochloric acidsolution, a saturated aqueous sodium hydrogen carbonate solution, andbrine, dried over sodium sulfate. The solvent was evaporated underreduced pressure, and the residue was purified by silica gel columnchromatography (hexane:ethyl acetate=1:0-3:2) to give1-(2,3,4,6-tetra-O-acetyl-β-D-glucopyranosyl)-4-chloro-3-(5-(5-fluoropyridin-2-yl)-2-thienylmethyl)benzene(218 mg) as a colorless solid. APCI-Mass m/Z 634/636 (M+H).

(4) The above1-(2,3,4,6-tetra-O-acetyl-β-D-glucopyranosyl)-4-chloro-3-(5-(5-fluoropyridin-2-yl)-2-thienylmethyl)benzene88 was treated in a manner similar to Example 106-(3) to give thedesired1-(β-D-glucopyranosyl)-4-chloro-3-(5-(5-fluoropyridin-2-yl)-2-thienylmethyl)benzene89 as a colorless solid. APCI-Mass m/Z 466/468 (M+H).

Example 1951-(β-D-glucopyranosyl)-3-(benzo[b]thiophen-2-ylmethyl)-indole

In the above scheme, the symbols are defined as above.

(1) 1-(β-D-glucopyranosyl)indole 90 (see Eur. J. Med. Chem. (2004) 39,453-458) was treated in a manner similar to Example 106-(1) to give1-(2,3,4,6-tetra-O-acetyl-β-D-glucopyranosyl)indole 91 as colorlesscrystals. APCI-Mass m/Z 465 (M+NH₄).

(2) Benzo[b]thiophene-2-carboxylic acid (598 mg) was suspended indichloromethane (10 ml). Added thereto were oxalyl chloride (0.39 ml)and N,N-dimethylformamide (one drop), and the mixture was stirred atroom temperature overnight. The solvent was evaporated under reducedpressure to give a corresponding acid chloride, which was dissolved indichloroethane (30 ml). To the solution was added1-(2,3,4,6-tetra-O-acetyl-β-D-glucopyranosyl)indole 91 (1 g) obtainedabove, and the mixture was cooled to 0° C. Added gradually thereto wasaluminum chloride (2.09 g), and subsequently, the mixture was stirred atthe same temperature for 30 minutes. The reaction mixture was pouredinto ice-cold water, and the mixture was extracted with chloroform. Theextract was washed successively with water, a saturated aqueous sodiumhydrogen carbonate solution and brine, dried over sodium sulfate, andthe solvent was evaporated under reduced pressure. The residue waspurified by silica gel column chromatography (hexane:ethylacetate=9:1-5:4) to give Benzo[b]thiophen-2-yl(1-(2,3,4,6-tetra-O-acetyl-β-D-glucopyranosyl)-indol-3-yl)ketone 92 (570mg) as colorless crystals. APCI-Mass m/Z 608 (M+H).

(3) The above Benzo[b]thiophen-2-yl(1-(2,3,4,6-tetra-O-acetyl-β-D-glucopyranosyl)-indol-3-yl)ketone 92 (440mg) was dissolved in tetrahydrofuran (6 ml) and ethanol (3 ml). To thesolution was added sodium borohydride (137 mg), and the mixture wasstirred at room temperature for 60 minutes. The reaction mixture wasquenched with cold aqueous HCl solution (0.5 N), and extracted withethyl acetate. The extract was washed successively with water, asaturated aqueous sodium hydrogen carbonate solution and brine, anddried over sodium sulfate. The solvent was evaporated under reducedpressure. The resultant residue was dissolved in dichloromethane (8 ml)and acetonitrile (4 ml), and the mixture was cooled to 0° C. under argonatmosphere. To the mixture were added triethylsilane (0.58 ml) and borontrifluoride.diethyl ether complex (0.46 ml). After 30 minutes, themixture was basified with a saturated aqueous sodium hydrogen carbonatesolution, and the organic layer was collected, dried over magnesiumsulfate, and the solvent was evaporated under reduced pressure. Theresultant residue was dissolved in chloroform (20 ml), and to themixture were added acetic anhydride (0.16 ml), triethylamine (0.2 ml),and 4-dimethylaminopyridine (15 mg), and the mixture was stirred at roomtemperature for 30 minutes. Then, the solution was washed successivelywith 10% aqueous hydrochloric acid solution, water, a saturated aqueoussodium hydrogen carbonate solution, and brine, and dried over magnesiumsulfate. The solvent was evaporated under reduced pressure, and theresultant residue was purified by silica gel column chromatography(hexane:ethyl acetate=8:2-6:4) to give1-(2,3,4,6-tetra-O-acetyl-β-D-glucopyranosyl)-3-(benzo-[b]thiophen-2-ylmethyl)indole93 (290 mg). APCI-Mass m/Z 611 (M+NH₄).

(4) The above1-(2,3,4,6-tetra-O-acetyl-β-D-glucopyranosyl)-3-(benzo[b]thiophen-2-ylmethyl)indole93 (336 mg) was treated in a manner similar to Example 106-(3) to givethe desired 1-(β-D-glucopyranosyl)-3-(benzo[b]thiophen-2-ylmethyl)indole94 (208 mg) as a colorless powder. APCI-Mass m/Z 443 (M+NH₄).

Example 1961-(β-D-glucopyranosyl)-3-(5-(3-cyanophenyl)-2-thienylmethyl)-4-fluoronaphthalene

(1) The1-(β-D-glucopyranosyl)-3-(5-chloro-2-thienylmethyl)-4-fluoronaphthaleneobtained in Example 137 was treated in a manner similar to Example106-(1) to give1-(2,3,4,6-tetra-O-acetyl-β-D-glucopyranosyl)-3-(5-chloro-2-thienylmethyl)-4-fluoronaphthalene.APCI-Mass m/Z 624/626 (M+NH₄).

(2) The above1-(2,3,4,6-tetra-O-acetyl-β-D-glucopyranosyl)-3-(5-chloro-2-thienylmethyl)-4-fluoronaphthalenewas treated in a manner similar to Example 158-(1) to give1-(2,3,4,6-tetra-O-acetyl-β-D-glucopyranosyl)-3-(2-thienylmethyl)-4-fluoronaphthalene.APCI-Mass m/Z 590 (M+NH₄).

(3) The above1-(2,3,4,6-tetra-O-acetyl-β-D-glucopyranosyl)-3-(2-thienylmethyl)-4-fluoronaphthalenewas treated in a manner similar to Example 19-(1) to give1-(2,3,4,6-tetra-O-acetyl-β-D-glucopyranosyl)-3-(5-bromo-2-thienylmethyl)-4-fluoronaphthalene.APCI-Mass m/Z 668/670 (M+NH₄).

(4) The above1-(2,3,4,6-tetra-O-acetyl-β-D-glucopyranosyl)-3-(5-bromo-2-thienylmethyl)-4-fluoronaphthaleneand 3-cyanophenylboronic acid were treated in a manner similar toExample 168 to give1-(β-D-glucopyranosyl)-3-(5-(3-cyanophenyl)-2-thienylmethyl)-4-fluoronaphthalene.APCI-Mass m/Z 523 (M+NH₄).

Example 1971-(β-D-glucopyranosyl)-3-(5-(4-aminophenyl)-2-thienylmethyl)-4-chlorobenzene

(1)1-(2,3,4,6-Tetra-O-acetyl-β-D-glucopyranosyl)-3-(5-bromo-2-thienylmethyl)-4-chlorobenzeneobtained in Example 128-(4) and4-(4,4,5,5-tetramethyl-1,3-dioxaborolan-2-yl)aniline were treated in amanner similar to Example 168-(1) to give1-(2,3,4,6-tetra-O-acetyl-β-D-glucopyranosyl)-3-(5-(4-aminophenyl)-2-thienylmethyl)-4-chlorobenzeneas pale yellow powder. APCI-Mass m/Z 630/632 (M+H).

(2) The above1-(2,3,4,6-tetra-O-acetyl-β-D-glucopyranosyl)-3-(5-(4-aminophenyl)-2-thienylmethyl)-4-chlorobenzenewas treated in a manner similar to Example 106-(3) to give the desired1-(β-D-glucopyranosyl)-3-(5-(4-aminophenyl)-2-thienylmethyl)-4-chlorobenzeneas pale yellow foam. APCI-Mass m/Z 479/481 (M+NH₄).

Example 1981-(β-D-glucopyranosyl)-4-chloro-3-(5-(4-methylcarbamoyl-phenyl)-2-thienylmethyl)benzene

(1)1-(β-D-Glucopyranosyl)-3-(5-(4-carboxyphenyl)-2-thienylmethyl)-4-chlorobenzene(637 mg) obtained in Example 192 was dissolved in a mixture ofdichloromethane (10 ml)-tetrahydrofuran (5 ml) and added thereto wereacetic anhydride (1.22 ml), pyridine (1.05 ml) and4-dimethylaminopyridine (32 mg). The mixture was stirred at roomtemperature overnight. The solvents were evaporated under reducedpressure and the residue was dissolved in ethyl acetate. The organiclayer was washed with 2N hydrochloric acid aqueous solution andsuccessively washed with brine. After drying over magnesium sulfate, thesolvent was evaporated under reduced pressure. The residue was purifiedby silica gel column chromatography (chloroform:methanol=100:1-50:1) togive1-(2,3,4,6-tetra-O-acetyl-β-D-glucopyranosyl)-3-(5-(4-carboxyphenyl)-2-thienylmethyl)-4-chlorobenzene(687 mg) as pale yellow powder. ESI-Mass m/Z 657/659 (M−H).

(2) The above1-(2,3,4,6-tetra-O-acetyl-β-D-glucopyranosyl)-3-(5-(4-carboxyphenyl)-2-thienylmethyl)-4-chlorobenzene(198 mg) was dissolved in dichloromethane (5 ml) and added thereto wereoxalyl chloride (1 ml) and N,N-dimethylformamide (one drop), and themixture was stirred at room temperature for 3.5 hours. The solvent wasevaporated under reduced pressure to give a corresponding acid chloride,which was suspended in tetrahydrofuran (4 ml), without furtherpurification. To the suspension was added a 2.0 M solution ofmethylamine in tetrahydrofuran (1.5 ml), and the mixture was stirred atroom temperature for 2 hours. The solvent was evaporated under reducedpressure, and the residue was purified by silica gel columnchromatography (chloroform:methanol=100:1) to give1-(2,3,4,6-tetra-O-acetyl-β-D-glucopyranosyl)-4-chloro-3-(5-(4-methylcarbamoylphenyl)-2-thienylmethyl)benzene(218 mg) as pale yellow powder. APCI-Mass m/Z 689/691 (M+NH₄).

(3) The above1-(2,3,4,6-tetra-O-acetyl-β-D-glucopyranosyl)-4-chloro-3-(5-(4-methylcarbamoylphenyl)-2-thienylmethyl)-benzenewas treated in a manner similar to Example 106-(3) to give the desired1-(β-D-glucopyranosyl)-4-chloro-3-(5-(4-methylcarbamoylphenyl)-2-thienylmethyl)benzeneas colorless powder. APCI-Mass m/Z 521/523 (M+NH₄).

Example 1991-(β-D-glucopyranosyl)-4-chloro-3-(5-(4-methylsulfonyl-aminophenyl)-2-thienylmethyl)benzene

(1)1-(2,3,4,6-Tetra-O-acetyl-β-D-glucopyranosyl)-3-(5-(4-aminophenyl)-2-thienylmethyl)-4-chlorobenzene(126 mg) obtained in Example 197-(1) was dissolved in dichloromethane (3ml) and added thereto were methanesulfonyl chloride (48 mg) and pyridine(48 mg). The mixture was stirred at room temperature for 3.5 hours. Tothe mixture was added 2N hydrochloric acid aqueous solution at 0° C. andextracted with ethyl acetate. The organic layer was washed with water,aqueous sodium hydrogen carbonate solution and successively washed withbrine. After drying over magnesium sulfate, the solvent was evaporatedunder reduced pressure. The residue was purified by silica gel columnchromatography (hexane:ethyl acetate=1:1-1:2) to give1-(2,3,4,6-tetra-O-acetyl-β-D-glucopyranosyl)-4-chloro-3-(5-(4-methylsulfonylaminophenyl)-2-thienylmethyl)benzene(154 mg) as yellow caramel. ESI-Mass m/Z 706/708 (M−H).

(2) The above1-(2,3,4,6-tetra-O-acetyl-β-D-glucopyranosyl)-4-chloro-3-(5-(4-methylsulfonylaminophenyl)-2-thienylmethyl)benzenewas treated in a manner similar to Example 106-(3) to give the desired1-(β-D-glucopyranosyl)-4-chloro-3-(5-(4-methylsulfonylaminophenyl)-2-thienylmethyl)benzeneas yellow foam. ESI-Mass m/Z 538/540 (M−H).

Example 2001-(β-D-glucopyranosyl)-3-(5-(4-acetylaminophenyl)-2-thienylmethyl)-4-chlorobenzene

1-(2,3,4,6-Tetra-O-acetyl-β-D-glucopyranosyl)-3-(5-(4-aminophenyl)-2-thienylmethyl)-4-chlorobenzene(126 mg) obtained in Example 197-(1) was treated in a manner similar toExample 106-(1) and (3) to give the target compound as colorless powder.APCI-Mass m/Z 521/523 (M+NH₄).

The compounds shown in Table 5 below were prepared in a manner similarto one of the above Examples from the corresponding starting materials.The numbers shown in a column of “preparation method” in the Tableindicates the Example number, according to which the preparation wascarried out.

TABLE 5

Examples

Preparation Method APCI-Mass (m/Z) 201

177 480 (M + NH₄) 202

168 500/502 (M + NH₄) 203

177 496/498 (M + NH₄) 204

128 454/456 (M + H) 205

168 500/502 (M + NH₄) 206

168 516/518 (M + NH₄) 207

128 454/456 (M + H) 208

164 458 (M + H) 209

177 458 (M + H) 210

164 434 (M + H) 211

177 450 (M + NH₄) 212

177 488 (M + NH₄) 213

1 482/484 (M + NH₄) 214

2 437/439 (M + H) 215

183 507/509 (M + NH₄) 216

168 466/468 (M + H) 217

177 446 (M + H) 218

164 434 (M + H) 219

185 487 (M + NH₄) 220

176 512 (M + NH₄) 221

168 530/532 (M + NH₄) 222

177 510 (M + NH₄) 223

2 504/506 (M + NH₄) 224

2 484 (M + NH₄) 225

186 470 (M + NH₄) 226

187 490/492 (M + NH₄) 227

2 417 (M + H) 228

1 462 (M + NH₄) 229

1 448 (M + NH₄) 230

1 480 (M + NH₄) 231

1 462 (M + NH₄) 232

177 488 (M + NH₄) 233

1 500/502 (M + NH₄) 234

168 494/496 (M + NH₄) 235

1 480 (M + NH₄) 236

168 530/532 (M + NH₄) 237

177 510 (M + NH₄) 238

1 448 (M + NH₄) 239

184 420/422 (M + H) 240

128 438/440 (M + H) 241

164 418 (M + H) 242

128 469/471 (M + NH₄) 243

1 434/436 (M + H) 244

128 468/470 (M + H) 245

189 473 (M + NH₄) 246

164 449 (M + NH₄) 247

168 483/485 (M + NH₄) 248

189 467 (M + NH₄) 249

168 492/494 (M + NH₄) 250

1 468/470 (M + NH₄) 251

168 499/501 (M + NH₄) 252

128 468/470 (M + H) 253

168 462/464 (M + H) 254

193 507/509 (M + NH₄) 255

196 517 (M + NH₄) 256

1 472/474 (M + H) 257

168 509/511 (M + NH₄) 258

168 490/492 (M + H) 259

198 535/537 (M + NH₄) 260

198 549/551 (M + NH₄)

The compounds shown in Table 6 below were prepared in a manner similarto Example 195 from the corresponding starting materials.

TABLE 6

Examples

APCI-Mass (m/Z) 261

449/451 (M + NH₄) 262

432/434 (M + H) 263

449/451 (M + NH₄)

Example 2641-(β-D-glucopyranosyl)-4-chloro-3-(5-(4-hydroxymethylphenyl)-2-thienylmethyl)benzene

1-(β-D-Glucopyranosyl)-4-chloro-3-(5-(4-formylphenyl)-2-thienylmethyl)benzene(84 mg) obtained in Example 249 was dissolved in a mixture of ethanol (2ml)-tetrahydrofuran (2 ml) and added thereto was sodium borohydride (7mg). The mixture was stirred at room temperature for 1 hour. The mixturewas quenched by 2N hydrochloric acid aqueous solution (3 drops) at 0°C., and the solvents were evaporated under reduced pressure. The residuewas purified by silica gel column chromatography(chloroform:methanol=9:1) to give the desired1-(β-D-glucopyranosyl)-4-chloro-3-(5-(4-hydroxymethylphenyl)-2-thienylmethyl)benzene(82 mg) as colorless foam. APCI-Mass m/Z 494/496 (M+NH₄).

Example 2651-(β-D-glucopyranosyl)-3-(5-phenyl-2-thienylmethyl)-4-methoxynaphthalene

(1)1-(β-D-Glucopyranosyl)-3-(5-chloro-2-thienylmethyl)-4-methoxynaphthaleneobtained in Example 250 was treated in a manner similar to Example106-(1) to give1-(2,3,4,6-tetra-O-acetyl-β-D-glucopyranosyl)-3-(5-chloro-2-thienylmethyl)-4-methoxynaphthalene.APCI-Mass m/Z 636/638 (M+NH₄).

(2) The above1-(2,3,4,6-tetra-O-acetyl-β-D-glucopyranosyl)-3-(5-chloro-2-thienylmethyl)-4-methoxynaphthalenewas treated in a manner similar to Example 158-(1) to give1-(2,3,4,6-tetra-O-acetyl-β-D-glucopyranosyl)-3-(2-thienylmethyl)-4-methoxynaphthalene.APCI-Mass m/Z 602 (M+NH₄).

(3) The above1-(2,3,4,6-tetra-O-acetyl-β-D-glucopyranosyl)-3-(2-thienylmethyl)-4-methoxynaphthalenewas treated in a manner similar to Example 159-(1) to give1-(2,3,4,6-tetra-O-acetyl-β-D-glucopyranosyl)-3-(5-bromo-2-thienylmethyl)-4-methoxynaphthalene.APCI-Mass m/Z 680/682 (M+NH₄).

(4) The above1-(2,3,4,6-tetra-O-acetyl-β-D-glucopyranosyl)-3-(5-bromo-2-thienylmethyl)-4-methoxynaphthaleneand phenylboronic acid were treated in a manner similar to Example 168to give the desired1-(β-D-glucopyranosyl)-3-(5-phenyl-2-thienylmethyl)-4-methoxynaphthalene.APCI-Mass m/Z 510 (M+NH₄).

Example 2661-(β-D-glucopyranosyl)-3-(5-(2-pyrimidinyl)-2-thienylmethyl)-4-methoxynaphthalene

1-(2,3,4,6-tetra-O-acetyl-β-D-glucopyranosyl)-3-(5-bromo-2-thienylmethyl)-4-methoxylnaphthaleneobtained in Example 265-(3) and 2-tributylstannylpyrimidine were treatedin a manner similar to Example 128-(5) and (6) to give1-(β-D-glucopyranosyl)-3-(5-(2-pyrimidinyl)-2-thienylmethyl)-4-methoxylnaphthalene.APCI-Mass m/Z 495 (M+H).

The compounds shown in Table 7 below were prepared in a manner similarto Example 265 from the corresponding starting materials.

TABLE 7

Ex- amples

APCI- Mass (m/Z) 267

535 (M + NH₄) 268

529 (M + NH₄)

Reference Example 1 3-Bromo-1-(5-ethyl-2-thienylmethyl)benzene

(1) A solution of 1,3-dibromobenzene (3.7 g) in tetrahydrofuran (25 ml)was cooled to −78° C. under argon atmosphere, and thereto was addeddropwise n-butyl lithium (2.44 M hexane solution, 5.55 ml). The reactionmixture was stirred at the same temperature for 10 minutes, and theretowas added dropwise a solution of 5-ethyl-2-thiophenecarboxaldehyde (2.0g) in tetrahydrofuran (10 ml). The mixture was stirred at the sametemperature for 30 minutes, and thereto was added a saturated ammoniumchloride solution, and the reaction mixture was warmed to roomtemperature. The mixture was extracted with ethyl acetate, and theextract was dried over magnesium sulfate, and the solvent was evaporatedunder reduced pressure. The residue was purified by silica gel columnchromatography (hexane:ethyl acetate=97:3-85:15) to give3-bromophenyl-5-ethyl-2-thienylmethanol (2.97 g) as a pale yellow syrup.APCI-Mass m/Z 279/281 (M+H−H₂O).

(2) The above 3-bromophenyl-5-ethyl-2-thienylmethanol (2.90 g) wasdissolved in dichloromethane (38 ml), and the mixture was cooled to −78°C. under argon atmosphere. To the mixture were added triethylsilane(6.18 ml) and boron trifluoride diethyl ether complex (2.45 ml), and themixture was gradually warmed to room temperature over a period of onehour. The mixture was basified with a saturated aqueous sodium hydrogencarbonate solution, and the dichloromethane layer was collected, driedover magnesium sulfate, and the solvent was evaporated under reducedpressure. The residue was purified by silica gel column chromatography(hexane) to give the desired 3-bromo-(5-ethyl-2-thienylmethyl)benzene(2.57 g) as a colorless syrup. APCI-Mass m/Z 281/283 (M+H).

Reference Example 2 5-Bromo-1-(4-ethylphenylmethyl)-1H-pyridin-2-one

5-Bromo-1H-pyridin-2-one (1.04 g) and 4-ethylbenzyl bromide (1.43 g)were dissolved in N,N-dimethylformamide (15 ml), and thereto was addedpotassium carbonate (1.66 g). The mixture was stirred at roomtemperature overnight, diluted with ethyl acetate, and washedsuccessively with water and brine. The extract was dried over magnesiumsulfate, and the solvent was evaporated under reduced pressure. Theresidue was purified by silica gel column chromatography (hexane:ethylacetate=10:1-3:1) to give5-bromo-1-(4-ethylphenylmethyl)-1H-pyridin-2-one (1.58 g) as colorlesscrystals. APCI-Mass m/Z 292/294 (M+H).

Reference Example 3

In the above scheme, the symbols are as defined above.

(1) A solution of silylated glucal 75 (see Parker et al., Org. Lett.2000, 2, 497-499) (7.00 g) in tetrahydrofuran (70 ml) was cooled to −78°C. under argon atmosphere. Thereto was added dropwise t-butyl lithium(1.45 M pentane solution, 49.0 ml) over a period of 10 minutes. Themixture was stirred at the same temperature for 15 minutes, and thenwarmed to room temperature, and further stirred for 30 minutes. Themixture was cooled again to −78° C., and thereto was added trimethylborate (8.90 ml) in one portion. After 15 minutes, the reaction solutionwas warmed to room temperature over a period of one hour, and theretowas added water (100 ml) at 0° C. The mixture was stirred for 30minutes, and extracted twice with diethyl ether. The extract was washedwith water, and then washed with brine. The resultant was dried overmagnesium sulfate, and the solvent was evaporated under reduced pressureto give the compound 76, which was used in the subsequent reactionwithout further purification.

(2) The whole amount of the above compound 76 was dissolved in toluene(65 ml), and thereto was added pinacol (2.24 g). The mixture was stirredat room temperature under argon atmosphere for 17 hours. The reactionsolution was poured into water, and the mixture was extracted with ethylacetate, and the extract was washed with brine, dried over magnesiumsulfate. The solvent was evaporated under reduced pressure to give thecompound 7 (10.4 g) as a yellow semisolid, which was used in thesubsequent reaction without further purification. APCI-Mass m/Z 569(M+H).

Reference Example 4 5-Bromo-2-methylbenzaldehyde

(1) Methyl 5-bromo-2-methylbenzoate (see Japanese Unexamined PatentPublication No. 9-263549) (16.12 g) was dissolved in methanol (100 ml),and thereto was added 10% aqueous sodium hydroxide solution (50 ml). Themixture was stirred at 50° C. for 40 minutes. Under ice-cooling, themixture was adjusted to pH 1 by addition of 10% aqueous hydrochloricacid solution, and diluted with water. Precipitated powder was collectedby filtration, and dried to give 5-bromo-2-methylbenzoic acid (14.1 g).ESI-Mass m/Z 213/215 (M−H).

(2) The above 5-bromo-2-methylbenzoic acid (10.0 g) was suspended indichloromethane (100 ml), and thereto were added oxalyl chloride (8.1ml) and N,N-dimethylformamide (2 drops). The mixture was stirred at roomtemperature for 4 hours. The solvent was evaporated under reducedpressure to give 5-bromo-2-methylbenzoyl chloride. This benzoyl chloridewas dissolved in dichloromethane (200 ml), and thereto was addedN,O-dimethylhydroxylamine hydrochloride (12.3 g). To the mixture wasadded dropwise triethylamine (20 ml) at 0° C., and the mixture wasstirred at room temperature overnight. The solvent was evaporated underreduced pressure, and the residue was extracted with ethyl acetate, andwashed successively with water, 10% aqueous hydrochloric acid solution,water, a saturated aqueous sodium hydrogen carbonate solution, andbrine. The extract was dried over sodium sulfate, and the solvent wasevaporated under reduced pressure to giveN-methoxy-N-methyl-5-bromo-2-methylbenzamide (12.25 g) as oil. APCI-Massm/Z 258/260 (M+H).

(3) A solution of the above N-methoxy-N-methyl-5-bromo-2-methylbenzamide(12.2 g) in tetrahydrofuran (100 ml) was cooled to −78° C. under argonatmosphere. To the mixture was added dropwise diisobutyl aluminumhydride (1.0 M toluene solution, 75 ml), and the mixture was stirred atthe same temperature for one hour. 10% aqueous hydrochloric acidsolution (50 ml) was added thereto, and the mixture was warmed to roomtemperature. The mixture was extracted with ethyl acetate twice, andwashed successively with a saturated aqueous sodium hydrogen carbonatesolution and brine. The extract was dried over magnesium sulfate, andthe solvent was evaporated under reduced pressure. The residue wassolidified to give 5-bromo-2-methylbenzaldehyde (8.73 g). APCI-Mass m/Z213/215 (M+H+MeOH−H₂O).

Reference Example 5 5-Bromo-2-chloro-1-(5-ethyl-2-thienylmethyl)benzene

(1) 5-Bromo-2-chlorobenzoic acid (5.00 g) was suspended indichloromethane (10 ml), and thereto were added oxalyl chloride (2.2 ml)and N,N-dimethylformamide (2 drops). The mixture was stirred at roomtemperature for 6 hours. The solvent was evaporated under reducedpressure to give 5-bromo-2-chlorobenzoyl chloride. This compound and2-ethylthiophene (2.38 g) were dissolved in dichloromethane (20 ml), andthereto was added aluminum chloride (3.11 g) at 0° C. The mixture wasstirred at the same temperature for one hour.

The reaction mixture was poured into a cold 10% aqueous hydrochloricacid solution, and the mixture was extracted with ethyl acetate. Theextract was washed successively with 10% aqueous hydrochloric acidsolution, water, a saturated aqueous sodium hydrogen carbonate solution,and brine, and dried over magnesium sulfate. The solvent was evaporatedunder reduced pressure, the residue was purified by silica gel columnchromatography (hexane:ethyl acetate=100:1) to give5-bromo-2-chlorophenyl 5-ethyl-2-thienyl ketone (5.29 g) as an oil.APCI-Mass m/Z 329/331 (M+H).

(2) A solution of the above 5-bromo-2-chlorophenyl 5-ethyl-2-thienylketone (5.29 g) in dichloromethane (50 ml)-acetonitrile (50 ml) wascooled under ice-cooling, and thereto were added dropwise triethylsilane(7.69 ml) and boron trifluoride.diethyl ether complex (6.1 ml).Subsequently, the mixture was stirred at room temperature for 3.5 hours,and was cooled again under ice-cooling. To the mixture was added asaturated aqueous sodium hydrogen carbonate solution, and the mixturewas extracted with chloroform, washed with brine, and dried overmagnesium sulfate. The solvent was evaporated under reduced pressure,and the residue was purified by silica gel column chromatography(hexane) to give 5-bromo-2-chloro-1-(5-ethyl-2-thienylmethyl)benzene(4.52 g) as a colorless liquid.

Reference Example 6 3-Bromo-1-(5-n-propyl-2-thienylmethyl)benzene

3-Bromobenzoic acid and 2-n-propylthiophene were used and treated in amanner similar to Reference Example 5 to give the target compound.

Reference Example 7 5-Bromo-(5-ethyl-2-thienylmethyl)-2-methoxybenzene

(1) A solution of 2-ethylthiophene (3.00 g) in tetrahydrofuran (36 ml)was cooled to 0° C. under argon atmosphere, and thereto was addeddropwise n-butyl lithium (1.56 M hexane solution, 17.1 ml). The mixturewas stirred at the same temperature for 30 minutes, and cooled to −78°C., and thereto was added dropwise a suspension of5-bromo-2-methoxybenzaldehyde (5.74 g) in tetrahydrofuran (60 ml). Themixture was stirred at the same temperature for 2 hours, warmed to 0°C., and thereto was added a saturated aqueous ammonium chloridesolution. The mixture was extracted with ethyl acetate, and the extractwas washed with brine, and dried over sodium sulfate. The solvent wasevaporated under reduced pressure. The residue was purified by silicagel column chromatography (hexane:ethyl acetate=100:0-85:15) to give5-bromo-2-methoxyphenyl-5-ethyl-2-thienylmethanol (5.99 g) as a paleyellow syrup. APCI-Mass m/Z 309/311 (M+H−H₂O).

(2) The above 5-bromo-2-methoxyphenyl-5-ethyl-2-thienylmethanol wastreated in a manner similar to Reference Example 1-(2) to give5-bromo-(5-ethyl-2-thienylmethyl)-2-methoxybenzene as oil. APCI-Mass m/Z311/313 (M+H).

Reference Example 8 3-Bromo-1-(5-ethyl-2-thienylmethyl)-4-methoxybenzene

2-Ethylthiophene and 3-bromo-4-methoxybenzaldehyde were used and treatedin a manner similar to Reference Example 7 to give the target compound.

Reference Example 9 3-Bromo-1-(4-n-propyl-2-thienylmethyl)benzene

(1) 3-n-Propylthiophene and 3-bromobenzaldehyde were used and treated ina manner similar to Reference Example 7-(1) to give3-bromophenyl-4-n-propyl-2-thienyl methanol. APCI-Mass m/Z 293/295(M+H−H₂O).

(2) A solution of the above 3-bromophenyl-4-n-propyl-2-thienyl methanol(2.4 g) in acetonitrile (10 ml) was added dropwise to a mixed solutionof chlorotrimethylsilane (4.54 ml) and sodium iodide (5.36 g) inacetonitrile (10 ml) at 0° C., over a period of 2 hours. The mixture wasfurther stirred at room temperature for 5 minutes, and cooled again to0° C. An aqueous solution (10 ml) of sodium hydroxide (1.0 g) was addedthereto, and the mixture was stirred at 0° C. for 0.5 hours. The mixturewas extracted with ethyl acetate, washed successively with an aqueoussodium thiosulfate solution, water and brine, and dried over sodiumsulfate. The solvent was evaporated under reduced pressure, and theresidue was purified by silica gel column chromatography (hexane) togive 3-bromo-1-(4-n-propyl-2-thienyl)benzene (1.97 g) as colorless oil.

Reference Example 105-Bromo-2-chloro-1-(5-n-propyl-2-thienylmethyl)benzene

5-Bromo-2-chlorobenozoic acid and 2-n-propylthiophene were used andtreated in a manner similar to Reference Example 5 to give the targetcompound.

Reference Example 115-Bromo-2-methoxy-1-(5-n-propyl-2-thienylmethyl)benzene

2-n-Propylthiophene and 5-bromo-2-methoxybenzaldehyde were used andtreated in a manner similar to Reference Example 7 to give the targetcompound. APCI-Mass m/Z 325/327 (M+H).

Reference Example 12 3-Bromo-1-(4-ethyl-2-thienylmethyl)benzene

3-Ethylthiophene and 3-bromobenzaldehyde were used and treated in amanner similar to Reference Example 9 to give the target compound.APCI-Mass m/Z 281/283 (M+H).

Reference Example 13 3-Bromo-1-(4-chloro-5-ethyl-2-thienylmethyl)benzene

(1) To a solution of 5-ethyl-2-thiophenecarboxaldehyde (6.0 g) inN,N-dimethylformamide (60 ml) was added N-chlorosuccinimide (8.57 g),and the mixture was stirred at room temperature for 2 hours, andsubsequently stirred under heating at 60° C. for 2 hours.N-chlorosuccinimide (4.00 g) was further added thereto, and the mixturewas further stirred under heating at 60° C. for 2 hours. The reactionmixture was poured into water, and the mixture was extracted with ethylacetate, washed with brine, and dried over sodium sulfate. The solventwas evaporated under reduced pressure, and the residue was purified bysilica gel column chromatography (hexane:ethyl acetate=33:1) to give4-chloro-5-ethyl-2-thiophenecarboxaldehyde (3.1 g) as colorless oil.

(2) The above 4-chloro-5-ethyl-2-thiophenecarboxaldehyde was treated ina manner similar to Reference Example 1 to give3-bromo-1-(4-chloro-5-ethyl-2-thienylmethyl)benzene as yellow oil.APCI-Mass m/Z 347/349 (M+H+MeOH).

Reference Example 145-Bromo-2-chloro-1-(4,5,6,7-tetrahydrobenzo[b]thiophen-2-ylmethyl)benzene

(1) To a solution of 4-keto-4,5,6,7-tetrahydrothianaphthene (9.83 g) inethylene glycol (100 ml) were added hydrazine hydrate (10.4 ml) andpotassium hydroxide (13.0 g), and the mixture was stirred under argonatmosphere at 190° C. for 4 hours. The reaction mixture was cooled toroom temperature, and poured into water, and the mixture was extractedwith ethyl acetate. The extract was washed with water, and dried oversodium sulfate. The solvent was evaporated under reduced pressure, andthe residue was purified by silica gel column chromatography (hexane) togive 4,5,6,7-tetrahydrothianaphthene (2.75 g) as colorless oil.

(2) The above 4,5,6,7-tetrahydrothianaphthene was treated in a mannersimilar to Reference Example 5 to give5-bromo-2-chloro-1-(4,5,6,7-tetrahydrobenzo[b]thiophen-2-yl-methylbenzeneas a colorless solid. APCI-Mass m/Z 341/343 (M+H).

Reference Example 155-Bromo-2-chloro-1-(5-ethyl-4-methyl-2-thienylmethyl)benzene

(3) 2-Acetyl-3-methylthiophene was treated in a manner similar toReference Example 14 to give the target compound. APCI-Mass m/Z 329/331(M+H).

Reference Example 165-Bromo-2-chloro-1-(2-thieno[3,2-b]thienylmethyl)benzene

(1) 5-Bromo-2-chlorobenzoic acid was treated in a manner similar toReference Example 4-(2) and (3) to give 5-bromo-2-chlorobenzaldehyde.APCI-Mass m/Z 233/235 (M+H+MeOH−H₂O).

(2) The above 5-bromo-2-chlorobenzaldehyde and thieno[3,2-b]thiophene(see Fuller, L.; Iddon, B.; Smith, K. A. J. Chem. Soc. Perkin Trans 11997, 3465-3470) were treated in a manner similar to Reference Example 9to give 5-bromo-2-chloro-1-(2-thieno[3,2-b]thienylmethyl)benzene ascolorless oil. APCI-Mass m/Z 343/345 (M+H).

Reference Example 175-Bromo-2-chloro-1-(5-chloro-2-thienylmethyl)benzene

2-Chlorothiophene was treated in a manner similar to Reference Example 5to give the target compound.

Reference Example 185-Bromo-2-chloro-1-(5-phenylmethyl-2-thienylmethyl)benzene

2-Benzoylthiophene was treated in a manner similar to Reference Example14 to give the target compound. APCI-Mass m/Z 377/379 (M+H).

Reference Example 195-Bromo-2-chloro-1-(5-(2-thienyl)-2-thienylmethyl)benzene

2,2′-Bithiophene and 5-bromo-2-chlorobenzaldehyde obtained in ReferenceExample 16-(1) were used and treated in a manner similar to ReferenceExample 9 to give the target compound. APCI-Mass m/Z 369/371 (M+H).

Reference Example 205-Bromo-1-(5-(5-chloro-2-thienyl)-2-thienylmethyl)-2-methylbenzene

(1) To a solution of 2-bromo-5-chlorothiophene (4.11 g),thiophene-2-boronic acid (4.00 g), tetrakis(triphenylphosphine)palladium(0) (1.20 g) and 2M aqueous sodium carbonate solution (31.3 ml) indimethoxyethane (100 ml) was heated under reflux under argon atmospherefor 2.5 hours. The reaction mixture was cooled, and extracted with ethylacetate. The solvent was evaporated under reduced pressure, and theresidue was purified by silica gel column chromatography (hexane) togive 2-(5-chloro-2-thienyl)thiophene (3.37 g) as pale yellow oil.

(2) The above 2-(5-chloro-2-thienyl)thiophene and5-bromo-2-methylbenzoic acid obtained in Reference Example 4-(1) wereused and treated in a manner similar to Reference Example 5 to give5-bromo-1-(5-(5-chloro-2-thienyl)-2-thienylmethyl)-2-methylbenzene as acolorless solid. APCI-Mass m/Z 383/385 (M+H).

Reference Example 215-Bromo-2-chloro-1-(4-chloro-5-ethyl-2-thienylmethyl)benzene

2-Acetyl-3-chlorothiophene (see Japanese Unexamined Patent PublicationNo. 2000-34230) was treated in a manner similar to Reference Example 14to give the target compound. APCI-Mass m/Z 347/349 (M+H).

Reference Example 22 5-Chloro-4-methylthiophene

The target compound was prepared according to a method described inJapanese Unexamined Patent Publication No. 10-324632.

Reference Example 235-Bromo-2-chloro-1-(5-(5-chloro-2-thienyl)-2-thienylmethyl)benzene

2-(5-Chloro-2-thienyl)thiophene and 5-bromo-2-chlorobenzoic acid weretreated in a manner similar to Reference Example 5 to give the targetcompound.

Reference Example 245-Bromo-2-chloro-1-(5-trifluoromethyl-2-thienylmethyl)benzene

2-Trifluoromethylthiophene (see Japanese Unexamined Patent PublicationNo. 2000-34239) and 5-bromo-2-chlorobenzaldehyde obtained in ReferenceExample 16-(1) were treated in a manner similar to Reference Example 7to give the target compound.

Reference Example 255-Bromo-2-chloro-1-(5-(2-pyridyl)-2-thienylmethyl)benzene

(1) 2-(2-Pyridyl)thiophene and 5-bromo-2-chlorobenzaldehyde obtained inReference Example 16-(1) were treated in a manner similar to ReferenceExample 7-(1) to give5-bromo-2-chlorophenyl-5-(2-pyridyl)-2-thienylmethanol as colorlesspowder. APCI-Mass m/Z 380/382 (M+H).

(2) A solution of the above5-bromo-2-chlorophenyl-5-(2-pyridyl)-2-thienylmethanol (3.52 g) intrifluoroacetic acid (45 ml) was added to a solution of sodiumborohydride (1.75 g) in trifluoroacetic acid (45 ml), and the mixturewas stirred at room temperature for 4 hours. Trifluoroacetic acid wasevaporated under reduced pressure. The residue was basified with anaqueous potassium hydroxide solution, and extracted with diethyl ether.The extract was dried over sodium sulfate, and the solvent wasevaporated under reduced pressure. The residue was purified by silicagel column chromatography (hexane:ethyl acetate=9:1-4:1) to give5-bromo-2-chloro-1-(5-(2-pyridyl)-2-thienylmethyl)benzene (2.42 g) as acolorless solid. APCI-Mass m/Z 364/366 (M+H).

Reference Example 265-Bromo-1-(5-chloro-2-thienylmethyl)-2-phenylbenzene

(1) 5-Bromo-2-iodobenzoic acid (see Jorg Frahn, A.-Dieter SchluterSynthesis 1997, 1301-1304) and 2-chlorothiophene were treated in amanner similar to Reference Example 5 to give5-bromo-1-(5-chloro-2-thienylmethyl)-2-iodobenzene as colorless oil.

(2) To a solution of the above5-bromo-1-(5-chloro-2-thienylmethyl)-2-iodobenzene (1.0 g) indimethoxyethane (10 ml) were added phenylboronic acid (310 mg),bis(triphenylphosphine)palladium (II)dichloride (85 mg) and 2M aqueoussodium carbonate solution (3.8 ml), and the mixture was stirred at 50°C. overnight. Added thereto was a saturated aqueous sodium hydrogencarbonate solution and the mixture was extracted with ethyl acetate anddried over sodium sulfate. The solvent was evaporated under reducedpressure, and the residue was purified by silica gel columnchromatography (hexane) to give5-bromo-1-(5-chloro-2-thienylmethyl)-2-phenylbenzene (683 mg) as oil.

Reference Example 27 2-Chlorothieno[3,2-b]thiophene

(1) A solution of thieno[3,2-b]thiophene (see Fuller, L.; Iddon, B.;Smith, K. A. J. Chem. Soc. Perkin Trans 1 1997, 3465-3470) (1.27 g) intetrahydrofuran (30 ml) was cooled to −78° C. under argon atmosphere,and thereto was added dropwise n-butyl lithium (1.59 M hexane solution,5.70 ml). The mixture was stirred at 0° C. for 30 minutes, and cooledagain to −78° C. Added thereto was a solution of hexachloroethane (2.14g) in tetrahydrofuran (5 ml). The mixture was stirred at the sametemperature for one hour, and warmed to 0° C. Added thereto was asaturated aqueous ammonium chloride solution, and the mixture wasextracted with ethyl acetate. The solvent was evaporated under reducedpressure. The residue was purified by silica gel column chromatography(hexane) to give 2-Chlorothieno[3,2-b]thiophene (1.19 g) as a solid.

Reference Example 281-(Benzo[b]thiophen-2-ylmethyl)-5-bromo-2-methoxybenzene

Thianaphthene was treated in a manner similar to Reference Example 7 togive the target compound. ESI-Mass m/Z 331/333 (M−H).

Reference Example 291-(Benzo[b]thiophen-2-ylmethyl)-5-bromo-2-chlorobenzene

Thianaphthene and 5-bromo-2-chlorobenzaldehyde obtained in ReferenceExample 16-(1) were treated in a manner similar to Reference Example 7to give the target compound.

Reference Example 303-Bromo-1-(5-methylbenzo[b]thiophen-2-ylmethyl)benzene

5-Methylbenzo[b]thiophene and 3-bromobenzaldehyde were treated in amanner similar to Reference Example 7 to give the target compound.

Reference Example 313-Bromo-1-(6-fluorobenzo[b]thiophen-2-ylmethyl)benzene

(1) To a solution of 2,4-difluorobenzaldehyde (5.0 g) indimethylsulfoxide (100 ml) were added methyl thioglycolate (3.45 ml) andtriethylamine (10 ml), and the mixture was stirred at 80° C. overnight.The reaction mixture was poured into ice-cold water. The mixture wasextracted with ethyl acetate, washed with water and brine, and driedover sodium sulfate. The solvent was evaporated under reduced pressure.The residue was purified by silica gel column chromatography(hexane:ethyl acetate=7:1) to give6-fluoro-2-methoxycarbonylbenzo[b]thiophene (1.32 g) as colorlesspowder. GC-EI-Mass m/Z 210 (M).

(2) The above 6-fluoro-2-methoxycarbonylbenzo[b]thiophene was treated ina manner similar to Reference Example 4-(1) to give6-fluorobenzo[b]thiophen-2-ylcarboxylic acid as colorless powder.ESI-Mass m/Z 195 (M−H).

(3) The above 6-fluorobenzo[b]thiophen-2-ylcarboxylic acid was treatedin a manner similar to Reference Example 4-(2) to give6-fluoro-2-(N-methoxy-N-methylcarbamoyl)benzo[b]thiophene as colorlesspowder. APCI-Mass m/Z 240 (M+H).

(4) A solution of 1,3-dibromobenzene (493 mg) in tetrahydrofuran (10 ml)was cooled to −78° C. under argon atmosphere, and thereto was addeddropwise n-butyl lithium (2.44 M hexane solution, 0.86 ml). The reactionmixture was stirred at the same temperature for 30 minutes, and theretowas added dropwise a solution of the above6-fluoro-2-(N-methoxy-N-methylcarbamoyl)benzo[b]thiophene (500 mg) intetrahydrofuran (3 ml). The mixture was warmed to room temperature, andadded thereto was a saturated aqueous ammonium chloride solution. Themixture was extracted with ethyl acetate, and dried over magnesiumsulfate. The solvent was evaporated under reduced pressure. The residuewas purified by silica gel column chromatography (hexane:ethylacetate=95:5-85:15) to give 3-bromophenyl 6-fluorobenzo[b]thiophen-2-ylketone (479 mg) as a pale yellow solid. APCI-Mass m/Z 335/337 (M+NH₄).

(5) The above 3-bromophenyl 6-fluorobenzo[b]thiophen-2-yl ketone wastreated in a manner similar to Reference Example 5-(2) to give3-bromo-1-(6-fluorobenzo[b]thiophen-2-ylmethyl)benzene as a colorlesssolid.

Reference Example 321-(Benzo[b]thiophen-2-ylmethyl)-3-bromo-4-fluorobenzene

Thianaphthene and 3-bromo-4-fluorobenzaldehyde were treated in a mannersimilar to Reference Example 7 to give the target compound.

Reference Example 331-(Benzo[b]thiophen-2-ylmethyl)-5-bromo-2-ethoxybenzene

Thianaphthene and 5-bromo-2-ethoxybenzaldehyde were treated in a mannersimilar to Reference Example 7 to give the target compound.

Reference Example 341-(Benzo[b]thiophen-2-ylmethyl)-5-bromo-2-fluorobenzene

Thianaphthene and 5-bromo-2-fluorobenzaldehyde were treated in a mannersimilar to Reference Example 7 to give the target compound.

Reference Example 352-(Benzo[b]thiophen-2-ylmethyl)-4-bromo-1-methoxynaphthalene

2,4-Dibromo-1-methoxynaphthalene (see J. Clayden, et al. Org. Lett., 5,(2003) 831) and benzo[b]thiophene-2-carboxaldehyde were treated in amanner similar to Reference Example 1 to give the target compound.

Reference Example 363-Bromo-1-(5-trifluoromethylbenzo[b]thiophen-2-ylmethyl)benzene

5-Trifluoromethylbenzo[b]thiophen-2-ylcarboxylic acid was treated in amanner similar to Reference Example 31-(3), (4), and (5) to give thetarget compound.

Reference Example 373-Bromo-1-(3-methylbenzo[b]thiophen-2-ylmethyl)benzene

3-Methylbenzo[b]thiophene-2-carboxaldehyde was treated in a mannersimilar to Reference Example 1 to give the target compound.

Reference Example 383-Bromo-1-(5-fluorobenzo[b]thiophen-2-ylmethyl)benzene

2,5-Difluorobenzaldehyde was treated in a manner similar to ReferenceExample 31 to give the target compound.

Reference Example 391-(Benzo[b]thiophen-2-ylmethyl)-3-bromo-4-methylbenzene

(1) 3-Bromo-4-methylbenzoic acid was treated in a manner similar toReference Example 4-(2) and (3) to give 3-bromo-4-methylbenzaldehyde ascolorless crystals. APCI-Mass m/Z 213/215 (M+H+MeOH).

(2) The above 3-bromo-4-methylbenzaldehyde and thianaphthene weretreated in a manner similar to Reference Example 7 to give(Benzo[b]thiophen-2-ylmethyl)-3-bromo-4-methylbenzene as a colorlesssolid.

Reference Example 401-(Benzo[b]thiophen-2-ylmethyl)-3-bromo-5-methylbenzene

3,5-Dibromotoluene and benzo[b]thiophene-2-carboxaldehyde were treatedin a manner similar to Reference Example 1 to give the target compound.

Reference Example 415-Bromo-2-chloro-1-(5-methylbenzo[b]thiophen-2-ylmethyl)benzene

5-Methylbenzo[b]thiophene and 5-bromo-2-chlorobenzaldehyde obtained inReference Example 16-(1) were treated in a manner similar to ReferenceExample 7 to give the target compound.

Reference Example 425-Bromo-2-chloro-1-(7-methylbenzo[b]thiophen-2-ylmethyl)benzene

7-Methylbenzo[b]thiophene (see Tilak, B. D. Tetrahedron 9 (1960) 76-95)and 5-bromo-2-chlorobenzaldehyde obtained in Reference Example 16-(1)were treated in a manner similar to Reference Example 7 to give thetarget compound.

Reference Example 435-Bromo-2-chloro-1-(5-chlorobenzo[b]thiophen-2-ylmethyl)benzene

5-Chlorobenzo[b]thiophene (see Tilak, B. D. Tetrahedron 9 (1960) 76-95)and 5-bromo-2-chlorobenzaldehyde obtained in Reference Example 16-(1)were treated in a manner similar to Reference Example 7 to give thetarget compound.

Reference Example 445-Bromo-2-chloro-1-(5,7-dimethylbenzo[b]thiophen-2-ylmethyl)benzene

5,7-Dimethylbenzo[b]thiophene (see Yoshimura, Y. et al., J. Med. Chem.43 (2000) 2929-2937) and 5-bromo-2-chlorobenzaldehyde obtained inReference Example 16-(1) were treated in a manner similar to ReferenceExample 7 to give the target compound.

Reference Example 451-(Benzo[b]thiophen-2-ylmethyl)-5-bromo-2-methylbenezene

(1) A solution of thianaphthene (543 mg) in diethyl ether (20 ml) wascooled to 0° C. under argon atmosphere, and thereto was added dropwisen-butyl lithium (2.44 M hexane solution, 1.74 ml). The reaction mixturewas stirred at the same temperature for 3 hours. The reaction mixturewas added dropwise to a solution ofN-methoxy-N-methyl-5-bromo-2-methylbenzamide (1.15 g) obtained inReference Example 4-(2) in diethyl ether (10 ml) cooled to −78° C. Themixture was warmed to room temperature and stirred for one hour. Addedthereto was a saturated aqueous ammonium chloride solution. The mixturewas extracted with ethyl acetate, washed with brine, and dried oversodium sulfate. The solvent was evaporated under reduced pressure. Theresidue was purified by silica gel column chromatography (hexane:ethylacetate=100:0-95:5) to give 5-bromo2-methylphenyl benzo[b]thiophen-2-ylketone (995 mg) as a pale yellow syrup. APCI-Mass m/Z 331/333 (M+H).

(2) The above 5-bromo2-methylphenyl benzo[b]thiophen-2-yl ketone wastreated in a manner similar to Reference Example 5-(2) to give1-(benzo[b]thiophen-2-ylmethyl)-5-bromo-2-methylbenezene as colorlessoil.

Reference Example 465-Bromo-2-chloro-1-(6-methoxybenzo[b]thiophen-2-ylmethyl)benzene

6-Methoxybenzo[b]thiophene (see WO 97/25033) and5-bromo-2-chlorobenzaldehyde obtained in Reference Example 16-(1) weretreated in a manner similar to Reference Example 7 to give the targetcompound.

Reference Example 475-Bromo-2-chloro-1-(6-chlorobenzo[b]thiophen-2-ylmethyl)benzene

(1) 4-Chloro-2-fluorobenzaldehyde was treated in a manner similar toReference Example 31-(1) and (2) to give6-chlorobenzo[b]thiophen-2-ylcarboxylic acid as colorless crystals.ESI-Mass m/Z 211/213 (M−H).

(2) A solution of the above 6-chlorobenzo[b]thiophen-2-ylcarboxylic acid(3.0 g) and copper powder (1.2 g) in quinoline (20 ml) was stirred at210° C. for 40 minutes. The mixture was cooled to room temperature anddiluted with diethyl ether, and insoluble materials were filtered off.The filtrate was washed successively with 10% aqueous hydrochloric acidsolution and brine, and dried over magnesium sulfate. The solvent wasevaporated under reduced pressure, and the residue was purified bysilica gel column chromatography (hexane) to give6-chlorobenzo[b]thiophene (1.79 g) as colorless crystals.

(3) The above 6-chlorobenzo[b]thiophene and 5-bromo-2-chlorobenzaldehydeobtained in Reference Example 16-(1) were treated in a manner similar toReference Example 7 to give5-bromo-2-chloro-1-(6-chlorobenzo[b]thiophen-2-ylmethyl)benzene ascolorless crystals.

Reference Example 485-Bromo-2-chloro-1-(6-trifluoromethylbenzo[b]thiophen-2-ylmethyl)benzene

2-Fluoro-4-trifluoromethylbenzaldehyde was treated in a manner similarto Reference Example 47 to give the target compound.

Reference Example 491-Benzo[b]thiophen-2-ylmethyl)-3-bromo-4-chlorobenzene

3-Bromo-4-chlorobenzoic acid was treated in a manner similar toReference Example 39 to give the target compound.

Reference Example 505-Bromo-2-chloro-1-(6-fluorobenzo[b]thiophen-2-ylmethyl)benzene

2,4-Difluorobenzaldehyde was treated in a manner similar to ReferenceExample 47 to give the target compound.

Reference Example 515-Bromo-2-fluoro-1-(6-fluorobenzo[b]thiophen-2-ylmethyl)benzene

6-Fluorobenzo[b]thiophene produced in the preparation process ofReference Example 50 and 5-bromo-2-fluorobenzaldehyde were treated in amanner similar to Reference Example 7 to give the target compound.

Reference Example 521-(Benzo[b]thiophen-2-ylmethyl)-3-bromo-5-chlorobenzene

1-Chloro-3,5-dibromobenzene and benzo[b]thiophene-2-carboxaldehyde weretreated in a manner similar to Reference Example 1 to give the targetcompound.

Reference Example 535-Bromo-2-chloro-1-(7-methoxybenzo[b]thiophen-2-ylmethyl)benzene

7-Methoxybenzo[b]thiophene (see WO 02/094262) and5-bromo-2-chlorobenzaldehyde obtained in Reference Example 16-(1) weretreated in a manner similar to Reference Example 9 to give the targetcompound. APCI-Mass m/Z 367/369 (M+H).

Reference Example 545-Bromo-2-chloro-1-(5-methoxybenzo[b]thiophen-2-ylmethyl)benzene

5-Methoxybenzo[b]thiophene (see WO 97/25033) and5-bromo-2-chlorobenzaldehyde obtained in Reference Example 16-(1) weretreated in a manner similar to Reference Example 9 to give the targetcompound. APCI-Mass m/Z 367/369 (M+H).

Reference Example 555-Bromo-2-chloro-1-(5-fluorobenzo[b]thiophen-2-ylmethyl)benzene

2,5-Difluorobenzaldehyde was treated in a manner similar to ReferenceExample 47 to give the target compound.

Reference Example 565-Bromo-2-chloro-1-(7-fluoro-6-methylbenzo[b]thiophen-2-ylmethyl)benzene

2,3-Difluoro-4-methylbenzaldehyde was treated in a manner similar toReference Example 47 to give the target compound. APCI-Mass m/Z 369/371(M+H).

Reference Example 575-Bromo-2-chloro-1-(4-fluorobenzo[b]thiophen-2-ylmethyl)benzene

2,6-Difluorobenzaldehyde was treated in a manner similar to ReferenceExample 47 to give the target compound.

Reference Example 585-Bromo-2-chloro-1-(7-fluorobenzo[b]thiophen-2-ylmethyl)benzene

2,3-difluorobenzaldehyde was treated in a manner similar to ReferenceExample 47 to give the target compound.

Reference Example 595-Bromo-2-chloro-1-(4-chlorobenzo[b]thiophen-2-ylmethyl)benzene

2-Chloro-6-fluorobenzaldehyde was treated in a manner similar toReference Example 47 to give the target compound.

Reference Example 605-Bromo-2-fluoro-1-(5-fluorobenzo[b]thiophen-2-ylmethyl)benzene

5-Fluorobenzo[b]thiophene produced in the preparation process ofReference Example 55 and 5-bromo-2-fluorobenzaldehyde were treated in amanner similar to Reference Example 7 to give the target compound.

Reference Example 613-Bromo-2-chloro-1-(benzo[b]thiophen-2-ylmethyl)benzene

(1) 3-Bromo-2-chlorobenzoic acid (see Frederic Gohier et al., J. Org.Chem. (2003) δ 2030-2033.) was treated in a manner similar to ReferenceExample 4-(2) to give N-methoxy-N-methyl-3-bromo-2-chlorobenzamide asoil. APCI-Mass m/Z 278/280/282 (M+H).

(2) The above N-methoxy-N-methyl-3-bromo-2-chlorobenzamide was treatedin a manner similar to Reference Example 45 to give3-bromo-2-chloro-1-(benzo[b]thiophen-2-ylmethyl)benzene as a colorlesssolid.

Reference Example 621-(Benzo[b]thiophen-2-ylmethyl)-5-bromo-2-ethylbenzene

(1) To a solution of 2-ethylbenzoic acid (10.0 g) in dichloromethane (50ml) were added oxalyl chloride (7.0 ml) and N,N-dimethylformamide (3drops) and the mixture was stirred at room temperature for 3 hours. Thesolvent was evaporated under reduced pressure to give a correspondingacid chloride. The acid chloride was dissolved in methanol (60 ml) andthe mixture was stirred at room temperature for 3 hours, and then, thesolvent was evaporated under reduced pressure. The residue was dissolvedin diethyl ether, and washed successively with a saturated aqueoussodium hydrogen carbonate solution and brine, and dried over sodiumsulfate. The solvent was evaporated under reduced pressure to givemethyl 2-ethylbenzoate, which was used in the subsequent step withoutfurther purification.

(2) The above methyl 2-ethylbenzoate was mixed with molecular sieve 13×(powder, 70 g), and while stirring the mixture, bromine (5.2 ml) wasadded dropwise thereto at 80° C. The mixture was further stirred at thesame temperature for 1.5 hours. The mixture was cooled to roomtemperature, and added thereto were potassium carbonate (7.4 g), water(70 ml) and methanol (350 ml), and the mixture was stirred for 8 hours.Insoluble materials were filtered off, and suspended in a mixed solutionof methanol (500 ml)-water (500 ml), and the mixture was stirred at roomtemperature overnight. Insoluble materials were filtered off and thefiltrate was combined with the previously obtained filtrate, and thesolvent was evaporated under reduced pressure. The residue was extractedwith ethyl acetate, and the extract was washed with brine, and driedover sodium sulfate. The solvent was evaporated under reduced pressure,and the residue was distilled under reduced pressure, to give methyl5-bromo-2-ethylbenzoate (2.44 g). APCI-Mass m/Z 260/262 (M+NH₄).

(3) The above methyl 5-bromo-2-ethylbenzoate was treated in a mannersimilar to Reference Example 4-(1) and (2) to giveN-methoxy-N-methyl-5-bromo-2-ethylbenzamide as colorless oil. APCI-Massm/Z 272/274 (M+H).

(4) The above N-methoxy-N-methyl-5-bromo-2-ethylbenzamide andthianaphthene were treated in a manner similar to Reference Example 45to give 1-(Benzo[b]thiophen-2-ylmethyl)-5-bromo-2-ethylbenzene as oil.

Reference Example 631-(Benzo[b]thiophen-2-ylmethyl)-5-bromo-2-trifluoromethylbenzene

(1) 5-Bromo-2-iodobenzoic acid (see Jorg Frahn, A.-Dieter SchluterSynthesis 1997, 1301-1304) was treated in a manner similar to ReferenceExample 4-(2) to give N-methoxy-N-methyl-5-bromo-2-iodobenzamide as apale yellow solid. APCI-Mass m/Z 370/372 (M+H).

(2) To a solution of the aboveN-methoxy-N-methyl-5-bromo-2-iodobenzamide (2.67 g) inN-methyl-2-pyrrolidinone (12 ml) were added copper (I) bromide (124 mg)and methyl fluorosulfonyl(difluoro)acetate (1.34 ml), and the mixturewas stirred under heating for 1.5 hours. The reaction mixture was cooledto room temperature, and then, a diluted aqueous ammonia was addedthereto, and the mixture was extracted with ethyl acetate. The extractwas washed with water and brine, and dried over sodium sulfate. Thesolvent was evaporated under reduced pressure. The residue was purifiedby silica gel column chromatography (hexane:ethyl acetate=100:0-85:15)to give N-methoxy-N-methyl-5-bromo-2-trifluoromethylbenzamide (1.59 g)as colorless oil. APCI-Mass m/Z 312/314 (M+H).

(3) The above N-methoxy-N-methyl-5-bromo-2-trifluoromethylbenzamide andthianaphthene were treated in a manner similar to Reference Example 45to give 1-(Benzo[b]thiophen-2-ylmethyl)-5-bromo-2-trifluoromethylbenzeneas a colorless solid. ESI-Mass m/Z 369/371 (M−H).

Reference Example 645-Bromo-2-chloro-1-(5-phenyl-2-thienylmethyl)benzene

2-Phenylthiophene was treated in a manner similar to Reference Example 5to give the target compound. APCI-Mass m/Z 363/365 (M+H).

Reference Example 655-Bromo-2-chloro-1-(5-(4-methylphenyl)-2-thienylmethyl)benzene

(1) 2-Iodothiophene and 4-methylphenylboronic acid were treated in amanner similar to Reference Example 26-(2) to give2-(4-methylphenyl)thiophene as colorless crystals. APCI-Mass m/Z 175(M+H).

(2) The above 2-(4-methylphenyl)thiophene was treated in a mannersimilar to Reference Example 5 to give5-bromo-2-chloro-1-(5-(4-methylphenyl)-2-thienylmethyl)benzene ascolorless crystals. APCI-Mass m/Z 377/379 (M+H).

Reference Example 665-Bromo-2-chloro-1-(5-(2-fluorophenyl)-2-thienylmethyl)benzene

(1) 2-Fluorobromobenzene and thiophene-2-boronic acid were treated in amanner similar to Reference Example 26-(2) to give2-(2-fluorophenyl)thiophene as a colorless liquid.

(2) The above 2-(2-fluorophenyl)thiophene was treated in a mannersimilar to Reference Example 5 to give5-bromo-2-chloro-1-(5-(2-fluorophenyl)-2-thienylmethyl)benzene as acolorless solid. APCI-Mass m/Z 381/383 (M+H).

Reference Example 675-Bromo-2-chloro-1-(5-(4-fluorophenyl)-2-thienylmethyl)benzene

(1) 2-Iodothiophene and 4-fluorophenylboronic acid were treated in amanner similar to Reference Example 26-(2) to give2-(4-fluorophenyl)thiophene as colorless powder.

(2) The above 2-(4-fluorophenyl)thiophene was treated in a mannersimilar to Reference Example 5 to give5-bromo-2-chloro-1-(5-(4-fluorophenyl)-2-thienylmethyl)benzene ascolorless powder.

Reference Example 685-Bromo-2-chloro-1-(5-(4-ethoxyphenyl)-2-thienylmethyl)benzene

(1) 2-Bromothiophene and 4-ethoxyphenylboronic acid were treated in amanner similar to Reference Example 20-(1) to give2-(4-ethoxyphenyl)thiophene as a colorless solid. APCI-Mass m/Z 205(M+H).

(2) The above 2-(4-ethoxyphenyl)thiophene was treated in a mannersimilar to Reference Example 5 to give5-bromo-2-chloro-1-(5-(4-ethoxyphenyl)-2-thienylmethyl)benzene as acolorless solid. APCI-Mass m/Z 407/409 (M+H).

Reference Example 695-Bromo-2-chloro-1-(5-(3-ethoxyphenyl)-2-thienylmethyl)benzene

(1) 2-Bromothiophene and 3-ethoxyphenylboronic acid were treated in amanner similar to Reference Example 20-(1) to give2-(3-ethoxyphenyl)thiophene as colorless oil. APCI-Mass m/Z 205 (M+H).

(2) The above 2-(3-ethoxyphenyl)thiophene and5-bromo-2-chlorobenzaldehyde obtained in Reference Example 16-(1) weretreated in a manner similar to Reference Example 9 to give5-bromo-2-chloro-1-(5-(3-ethoxyphenyl)-2-thienylmethyl)benzene ascolorless oil. APCI-Mass m/Z 407/409 (M+H).

Reference Example 705-Bromo-2-chloro-1-(5-(2-ethoxyphenyl)-2-thienylmethyl)benzene

(1) 2-Iodothiophene and 2-ethoxyphenylboronic acid were treated in amanner similar to Reference Example 26-(2) to give2-(2-ethoxyphenyl)thiophene as a pale yellow solid.

(2) The above 2-(2-ethoxyphenyl)thiophene and5-bromo-2-chlorobenzaldehyde obtained in Reference Example 16-(1) weretreated in a manner similar to Reference Example 9 to give5-bromo-2-chloro-1-(5-(2-ethoxyphenyl)-2-thienylmethyl)benzene ascolorless oil. APCI-Mass m/Z 407/409 (M+H).

Reference Example 715-Bromo-2-fluoro-1-(5-phenyl-2-thienylmethyl)benzene

2-Phenylthiophene and 5-bromo-2-fluorobenzaldehyde were treated in amanner similar to Reference Example 7 to give the target compound.APCI-Mass m/Z 347/349 (M+H).

Reference Example 725-Bromo-1-(5-(4-ethoxyphenyl)-2-thienylmethyl)-2-fluorobenzene

2-(4-Ethoxyphenyl)thiophene obtained in Reference Example 68-(1) and5-bromo-2-fluorobenzaldehyde were treated in a manner similar toReference Example 7 to give the target compound. APCI-Mass m/Z 391/393(M+H).

Reference Example 735-Bromo-1-(5-(2-ethoxyphenyl)-2-thienylmethyl)-2-fluorobenzene

2-(2-Ethoxyphenyl)thiophene obtained in Reference Example 70-(1) and5-bromo-2-fluorobenzaldehyde were treated in a manner similar toReference Example 9 to give the target compound. APCI-Mass m/Z 391/393(M+H).

Reference Example 745-Bromo-2-fluoro-1-(5-(2-fluorophenyl)-2-thienylmethyl)benzene

2-(2-Fluorophenyl)thiophene obtained in Reference Example 66-(1) and5-bromo-2-fluorobenzaldehyde were treated in a manner similar toReference Example 7 to give the target compound. APCI-Mass m/Z 365/367(M+H).

Reference Example 755-Bromo-2-chloro-1-(5-(3-fluorophenyl)-2-thienylmethyl)benzene

(1) 2-Iodothiophene and 3-fluorophenylboronic acid were treated in amanner similar to Reference Example 26-(2) to give2-(3-fluorophenyl)thiophene as oil.

(2) The above 2-(3-fluorophenyl)thiophene was treated in a mannersimilar to Reference Example 5 to give the target compound as powder.

Reference Example 765-Bromo-1-(5-(3-ethoxyphenyl)-2-thienylmethyl)-2-fluorobenzene

2-(3-Ethoxyphenyl)thiophene obtained in Reference Example 69-(1) and5-bromo-2-fluorobenzaldehyde were treated in a manner similar toReference Example 9 to give the target compound. APCI-Mass m/Z 391/393(M+H).

Reference Example 775-Bromo-2-fluoro-1-(5-(3-fluorophenyl)-2-thienylmethyl)benzene

2-(3-Fluorophenyl)thiophene obtained in Reference Example 75-(1) and5-bromo-2-fluorobenzaldehyde were treated in a manner similar toReference Example 7 to give the target compound.

Reference Example 785-Bromo-2-fluoro-1-(5-(4-fluorophenyl)-2-thienylmethyl)benzene

2-(4-Fluorophenyl)thiophene obtained in Reference Example 67-(1) and5-bromo-2-fluorobenzaldehyde were treated in a manner similar toReference Example 7 to give the target compound.

Reference Example 795-Bromo-2-methyl-1-(5-phenyl-2-thienylmethyl)benzene

2-Phenylthiophene and 5-bromo-2-methylbenzoic acid obtained in ReferenceExample 4-(1) were treated in a manner similar to Reference Example 5 togive the target compound. APCI-Mass m/Z 343/345 (M+H).

Reference Example 805-Bromo-1-(5-(3-fluorophenyl)-2-thienylmethyl)-2-methylbenzene

2-(3-Fluorophenyl)thiophene obtained in Reference Example 75-(1) and5-bromo-2-methylbenzoic acid obtained in Reference Example 4-(1) weretreated in a manner similar to Reference Example 5 to give the targetcompound.

Reference Example 815-Bromo-1-(5-(4-fluorophenyl)-2-thienylmethyl)-2-methylbenzene

2-(4-Fluorophenyl)thiophene obtained in Reference Example 67-(1) and5-bromo-2-methylbenzoic acid obtained in Reference Example 4-(1) weretreated in a manner similar to Reference Example 5 to give the targetcompound.

Reference Example 825-Bromo-2-methoxy-1-(5-phenyl-2-thienylmethyl)benzene

2-Phenylthiophene was treated in a manner similar to Reference Example 7to give the target compound. APCI-Mass m/Z 359/361 (M+H).

Reference Example 835-Bromo-2-methyl-1-(5-(3-methylphenyl)-2-thienylmethyl)benzene

(1) 2-Bromothiophene and 3-methylphenylboronic acid were treated in amanner similar to Reference Example 26-(2) to give2-(3-methylphenyl)thiophene as colorless oil.

(2) The above 2-(3-methylphenyl)thiophene and5-bromo-2-methylbenzaldehyde obtained in Reference Example 4 weretreated in a manner similar to Reference Example 9 to give the targetcompound. APCI-Mass m/Z 357/359 (M+H).

Reference Example 845-Bromo-2-chloro-1-(5-(3-methylphenyl)-2-thienylmethyl)benzene

2-(3-Methylphenyl)thiophene obtained in Reference Example 83-(1) and5-bromo-2-chlorobenzaldehyde obtained in Reference Example 16-(1) weretreated in a manner similar to Reference Example 9 to give the targetcompound. APCI-Mass m/Z 377/379/381 (M+H).

Reference Example 855-Bromo-2-chloro-1-(5-(3-chlorophenyl)-2-thienylmethyl)benzene

(1) 2-Bromothiophene and 3-chlorophenylboronic acid were treated in amanner similar to Reference Example 26-(2) to give2-(3-chlorophenyl)thiophene as colorless oil.

(2) The above 2-(3-chlorophenyl)thiophene was treated in a mannersimilar to Reference Example 5 to give the target compound as colorlessoil.

Reference Example 865-Bromo-1-(5-(3-chlorophenyl)-2-thienylmethyl)-2-methylbenzene

2-(3-Chlorophenyl)thiophene obtained in Reference Example 85-(1) and5-bromo-2-methylbenzoic acid obtained in Reference Example 4-(1) weretreated in a manner similar to Reference Example 5 to give the targetcompound as colorless oil.

Reference Example 875-Bromo-1-(5-(3-methoxyphenyl)-2-thienylmethyl)-2-methylbenzene

(1) 3-Methoxybromobenzene and thiophene-2-boronic acid were treated in amanner similar to Reference Example 26-(2) to give2-(3-methoxyphenyl)thiophene as a yellow liquid. APCI-Mass m/Z 191(M+H).

(2) The above 2-(3-methoxyphenyl)thiophene and5-bromo-2-methylbenzaldehyde obtained in Reference Example 4 weretreated in a manner similar to Reference Example 9 to give the targetcompound as yellow oil. APCI-Mass m/Z 373/375 (M+H).

Reference Example 884-Bromo-2-(4-ethylphenylmethyl)-2H-isoquinolin-1-one

4-Bromo-2H-isoquiolin-1-one (see EP0355750) was treated in a mannersimilar to Reference Example 2 to give the target compound. APCI-Massm/Z 342/344 (M+H).

Reference Example 894-Bromo-2-(4-ethylphenylmethyl)-8-methyl-2H-isoquinolin-1one

(1) To a solution of 8-methyl-2H-isoquiolin-1-one (1.15 g) indichloromethane (20 ml) was added dropwise a solution of bromine (1.26g) in dichloromethane (4 ml) at room temperature. The mixture wasstirred at the same temperature for one hour, and the solvent wasevaporated under reduced pressure. The residue was crystallized fromether to give 4-bromo-8-methyl-2H-isoquinolin-1-one (1.86 g) ascolorless crystals. APCI-Mass m/Z 238/240 (M+H).

(2) The above 4-bromo-8-methyl-2H-isoquinolin-1-one was treated in amanner similar to Reference Example 2 to give the target compound ascolorless crystals. APCI-Mass m/Z 356/358M+H).

Reference Example 90 4-Bromo-2-(4-ethylphenylmethyl)thiophene

(1) A solution of 4-bromo-2-thiophenecarboxaldehyde (4.78 g) intetrahydrofuran (40 ml) was cooled to 0° C. under argon atmosphere, andthereto was added dropwise 4-ethylphenylmagnesium bromide (0.5 Mtetrahydrofuran solution, 50 ml). The mixture was stirred at the sametemperature for 30 minutes, and thereto was added a saturated aqueousammonium chloride solution, and the mixture was extracted with ethylacetate. The extract was washed with brine and dried over magnesiumsulfate, and the solvent was evaporated under reduced pressure. Theresidue was purified by silica gel column chromatography (hexane:ethylacetate=97:3-84:16) to give 4-bromo-2-thienyl-4-ethylphenylmethanol(5.37 g) as colorless oil. APCI-Mass m/Z 279/281 (M+H−H₂O).

(2) The above 4-bromo-2-thienyl-4-ethylphenylmethanol was treated in amanner similar to Reference Example 1-(2) to give the target compound ascolorless oil.

Reference Example 91 5-Bromo-2-(4-ethylphenylmethyl)thiophene

5-Bromo-2-thiophenecarboxaldehyde was treated in a manner similar toReference Example 90 to give the target compound. ESI-Mass m/Z 279/281(M−H).

Reference Example 92 3-Bromo-2-(4-ethylphenylmethyl)thiophene

(1) 2,3-Dibromothiophene and 4-ethylbenzaldehyde were treated in amanner similar to Reference Example 1-(1) to give3-bromo-2-thienyl-4-ethylphenylmethanol as yellow oil. APCI-Mass m/Z279/281 (M+H−H₂O).

(2) A solution of the above 3-bromo-2-thienyl-4-ethylphenylmethanol(12.4 g) in diethyl ether (10 ml) was added dropwise into a suspensionof lithium aluminum hydride (2.6 g) and aluminum chloride (9.0 g) indiethyl ether (35 ml) at 0° C. Subsequently, the mixture was stirred atroom temperature overnight, and then poured onto ice. The mixture wasextracted with diethyl ether, washed with a saturated aqueous sodiumhydrogen carbonate solution, and dried over magnesium sulfate. Thesolvent was evaporated under reduced pressure, and the residue waspurified by silica gel column chromatography (hexane) to give3-bromo-2-(4-ethylphenylmethyl)thiophene (8.77 g) as colorless oil.APCI-Mass m/Z 279/281 (M+H).

Reference Example 93 5-Bromo-3-(4-ethylphenylmethyl)thiophene

5-Bromo-3-thiophenecarboxaldehyde (see Amishiro, N. et al., Chem. Pharm.Bull. 47 (1999) 1393-1403.) was treated in a manner similar to ReferenceExample 90 to give the target compound.

Reference Example 94 5-Bromo-2-chloro-3-(4-ethylphenylmethyl)thiophene

(1) 5-Bromo-2-chloro-3-thiophenecarboxylic acid (see Japanese UnexaminedPatent Publication No. 10-324632) was treated in a manner similar toReference Example 4-(2) and (3) to give5-bromo-2-chloro-3-thiophenecarboxaldehyde as pale yellow oil. APCI-Massm/Z 239/241/243 (M+H+MeOH−H₂O).

(2) The above 5-bromo-2-chloro-3-thiophenecarboxaldehyde was treated ina manner similar to Reference Example 90 to give the target compound ascolorless oil.

Reference Example 95 5-Bromo-3-chloro-2-(4-ethylphenylmethyl)thiophene

(1) A solution of diisopropylamine (6.8 ml) in tetrahydrofuran (75 ml)was cooled to −78° C. under argon atmosphere, and thereto was addeddropwise n-butyl lithium (1.59 M hexane solution, 30.5 ml). The reactionmixture was stirred at the same temperature for 30 minutes, and theretowas added dropwise a solution of 3-chloro-2-thiophenecarboxylic acid(3.92 g) in tetrahydrofuran (40 ml). The mixture was stirred at the sametemperature for 30 minutes, and thereto was added dropwise1,2-dibromo-1,1,2,2-tetrafluoroethane (6.0 ml). The mixture was stirredat the same temperature for one hour, and then, warmed to roomtemperature. The mixture was poured into a diluted aqueous hydrochloricacid solution, and the solution was extracted with ethyl acetate. Theextract was washed with brine, and dried over sodium sulfate. Thesolvent was evaporated under reduced pressure and the residue wascrystallized from a mixed solvent of diisopropyl ether and hexane togive 5-bromo-3-chloro-2-thiophenecarboxylic acid (3.79 g) as a yellowsolid. ESI-Mass m/Z 239/241 (M−H).

(2) The above 5-bromo-3-chloro-2-thiophenecarboxylic acid was treated ina manner similar to Reference Example 94 to give5-bromo-3-chloro-2-(4-ethylphenylmethyl)thiophene as colorless oil.

Reference Example 96 3-Bromo-1-(benzo[b]thiophen-3-ylmethyl)benzene

Thianaphthene-3-carboxaldehyde was treated in a manner similar toReference Example 1 to give the target compound.

Reference Example 97 3-Bromo-1-(5-ethyl-2-furylmethyl)benzene

(1) 5-Ethyl-2-furaldehyde was treated in a manner similar to ReferenceExample 1-(1) to give 3-bromophenyl-5-ethyl-2-furylmethanol as oil.APCI-Mass m/Z 263/265 (M+H−H₂O).

(2) The above 3-bromophenyl-5-ethyl-2-furylmethanol was treated in amanner similar to Reference Example 9-(2) to give the target compound asoil.

Reference Example 98 3-Bromo-1-(benzo[b]furan-2-ylmethyl)benzene

2-Benzo[b]furancarboxaldehyde was treated in a manner similar toReference Example 97 to give the target compound.

Reference Example 991-(Benzo[b]furan-2-ylmethyl)-5-bromo-2-chlorobenzene

Benzo[b]furan and 5-bromo-2-chlorobenzaldehyde obtained in ReferenceExample 16-(1) were treated in a manner similar to Reference Example 7to give the target compound.

Reference Example 1001-(Benzothiazol-2-ylmethyl)-5-bromo-2-methylbenzene

(1) Benzothiazole and 5-bromo-2-methylbenzaldehyde obtained in ReferenceExample 4 were treated in a manner similar to Reference Example 7-(1) togive 5-bromo-2-methylphenyl-(benzothiazol-2-yl)methanol as pale yellowcrystals. APCI-Mass m/Z 334/336 (M+H).

(2) To a solution of the above5-bromo-2-methylphenyl-(benzothiazol-2-yl)methanol (2.60 g) indichloromethane (30 ml)-toluene (10 ml) was added manganese(IV) oxide(3.42 g), and the mixture was stirred at room temperature for 3 hours.Insoluble materials were filtered off, and the filtrate was evaporatedunder reduced pressure to give 5-bromo-2-methylphenyl benzothiazol-2-ylketone (2.45 g) as colorless crystals. APCI-Mass m/Z 332/334 (M+H).

(3) The above 5-bromo-2-methylphenyl benzothiazol-2-yl ketone wastreated in a manner similar to Reference Example 14-(1) to give1-(benzothiazol-2-ylmethyl)-5-bromo-2-methylbenzene as oil. APCI-Massm/Z 318/320 (M+H).

Reference Example 1011-(Benzothiazol-2-ylmethyl)-5-bromo-2-chlorobenzene

Benzothiazole and 5-bromo-2-chlorobenzaldehyde obtained in ReferenceExample 16-(1) were treated in a manner similar to Reference Example 100to give the target compound. APCI-Mass m/Z 338/340 (M+H).

Reference Example 1025-Bromo-2-chloro-1-(5-phenyl-2-thiazolylmethyl)benzene

(1) A solution of thiazole (10.0 g), iodobenzene (2.63 ml),tetrakis(triphenylphosphine)palladium (0) (1.36 g) and potassium acetate(3.46 g) in N,N-dimethylacetamide (100 ml) was stirred under heating at100° C. overnight. The solvent was evaporated under reduced pressure,and added to the residue was ethyl acetate. The mixture was washedsuccessively with water and brine, and dried over sodium sulfate. Thesolvent was evaporated under reduced pressure, and the residue waspurified by silica gel column chromatography (hexane:ethylacetate=100:0-90:10) to give 5-phenylthiazole (1.50 g) as a pale yellowsolid. APCI-Mass m/Z 162 (M+H).

(2) The above 5-phenylthiazole and 5-bromo-2-chlorobenzaldehyde obtainedin Reference Example 16-(1) were treated in a manner similar toReference Example 100 to give5-bromo-2-chloro-1-(5-phenyl-2-thiazolylmethyl)benzene as a yellowsolid. APCI-Mass m/Z 364/366 (M+H).

Reference Example 103 3-(4-Ethylphenylmethyl)-2,4-pentanedione

A suspension of sodium iodide (15.0 g) in acetonitrile (100 ml) wascooled to 0° C. under argon atmosphere, and thereto were added dropwisechlorotrimethylsilane (12.7 ml), 2,4-pentanedione (2.05 ml) and4-ethylbenzaldehide (2.68 g), successively. The reaction mixture wasstirred at room temperature for 17 hours, and further stirred at 60° C.for 10 hours. The reaction mixture was cooled to room temperature andpoured into an aqueous sodium thiosulfate solution. The mixture wasextracted with diethyl ether, and the extract was washed with brine anddried over magnesium sulfate. The solvent was evaporated under reducedpressure and the residue was purified by silica gel columnchromatography (hexane:ethyl acetate=9:1) to give3-(4-ethylphenylmethyl)-2,4-pentanedione (2.72 g) as pale yellow oil.APCI-Mass m/Z 219 (M+H).

Reference Example 104 Tri-n-butyl(4-ethylphenyl)tin

To a solution of magnesium (896 mg) in tetrahydrofuran (20 ml) was addeddibromoethan (0.1 ml), and the mixture was stirred at room temperaturefor 15 minutes. Thereto was added dropwise a solution of1-bromo-4-ethylbenzene (5.7 g) in tetrahydrofuran (20 ml), andsubsequently, the mixture was stirred at room temperature for one hour.The reaction mixture was cooled to −78° C., and thereto was addeddropwise tributyltin chloride (9.49 g). The mixture was stirred at thesame temperature for 30 minutes, and then at room temperature for onehour. To the reaction mixture were added 10% aqueous potassium fluoridesolution and ethyl acetate, and the mixture was stirred at roomtemperature for 30 minutes. Insoluble materials were filtered off. Theorganic layer of the filtrate was washed with water and brinesuccessively, and dried over sodium sulfate. The solvent was evaporatedunder reduced pressure and the residue was purified by alumina columnchromatography (hexane) to give the desiredtri-n-butyl(4-ethylphenyl)tin (10.7 g) as colorless oil. EI-Mass m/Z 337(M-Bu).

Reference Example 105 4-(4-Ethylphenylmethyl)pyrazole

(1) A mixed solution of 4-ethylbenzyl bromide (10.0 g), malononitrile(6.64 g), potassium carbonate (6.94 g) and tetra-n-butylammonium bromide(648 mg) in toluene (100 ml) was agitated at room temperature for 17hours. The reaction mixture was poured into water, and the mixture wasextracted with ethyl acetate twice. The extract was washed successivelywith water and brine, and dried over sodium sulfate. The solvent wasevaporated under reduced pressure and the residue was purified by silicagel column chromatography (hexane:ethyl acetate=6:1) to give2-(4-ethylphenylmethyl)malononitrile (3.28 g) as a colorless solid.

(2) A solution of the above 2-(4-ethylphenylmethyl)malononitrile (1.30g) and hydrazine hydrate (0.86 ml) in ethanol (35 ml) was heated underreflux for 4 hours. Hydrazine hydrate (0.43 ml) was further addedthereto and the mixture was further heated under reflux for 4 hours. Thereaction mixture was cooled to room temperature and the solvent wasevaporated under reduced pressure. The residue was crystallized fromethyl acetate-diethyl ether to give3,5-diamino-4-(4-ethylphenylmethyl)pyrazole (2.63 g) as pale pinkpowder. APCI-Mass m/Z 217 (M+H).

(3) The above 3,5-diamino-4-(4-ethylphenylmethyl)pyrazole (1.30 g) wasadded to 50% aqueous phosphoric acid solution (19 ml), and further addedthereto was water (10 ml). The mixture was cooled to 0° C., and theretowas added dropwise an aqueous solution (4 ml) of sodium nitrite (912mg). The mixture was stirred at the same temperature for 30 minutes, andfurther stirred at room temperature for 4 hours. The reaction mixturewas cooled again to 0° C., 10% aqueous sodium hydroxide solution wasadded thereto to adjust pH of the reaction mixture to 7. The mixture wasextracted with ethyl acetate, washed successively with water and brine,and dried over magnesium sulfate. The solvent was evaporated underreduced pressure, and the residue was purified by silica gel columnchromatography (chloroform:methanol=100:0-90:10) to give the desired4-(4-ethylphenylmethyl)pyrazole (414 mg) as a pale brown semisolid.APCI-Mass m/Z 187 (M+H).

Reference Example 106 3-(4-Ethylphenylmethyl)-5-methyl-1H-pyrazole

(1) 4-Ethylphenylacetic acid (3.0 g) (see Japanese Unexamined PatentPublication 63-233975) was dissolved in dichloromethane (15 ml), andthereto were added oxalyl chloride (6.0 ml) and N,N-dimethylformamide(one drop). The mixture was stirred at room temperature for 1.5 hours.The reaction mixture was evaporated under reduced pressure, and theresidue was subjected to azeotropic distillation with toluene to give acrude 4-ethylphenylacetyl chloride, which was used in the subsequentstep without further purification.

(2) A suspension of magnesium chloride (1.74 g) in dichloromethane (30ml) was cooled to 0° C., and thereto were added t-butyl acetoacetate(3.03 ml) and pyridine (2.96 ml), and successively was added a solutionof the above 4-ethylphenylacetyl chloride in dichloromethane (30 ml).The mixture was stirred at the same temperature for 2.5 hours, and anaqueous citric acid solution was added thereto. The mixture wasextracted with chloroform. The extract was washed with brine, and driedover sodium sulfate. The solvent was evaporated under reduced pressure.The residue was purified by silica gel column chromatography(hexane:ethyl acetate=15:1) to give t-butyl2-acetyl-4-(4-ethylphenyl)-3-oxobutyrate (4.75 g) as pale yellow oil.APCI-Mass m/Z 322 (M+NH₄).

(3) A solution of the above t-butyl2-acetyl-4-(4-ethylphenyl)-3-oxobutyrate in trifluoroacetic acid (60 ml)was stirred at room temperature for 2 hours. The solvent was evaporatedunder reduced pressure, and the residue was dissolved in ethyl acetate,and the mixture was washed successively with a saturated aqueous sodiumhydrogen carbonate solution and brine. The mixture was dried over sodiumsulfate, and the solvent was evaporated under reduced pressure to give1-(4-ethylphenyl)-4-hydroxy-3-penten-2-one (4.00 g) as yellow oil.APCI-Mass m/Z 205 (M+H).

(4) A solution of the above 1-(4-ethylphenyl)-4-hydroxy-3-penten-2-one(3.98 g) and hydrazine hydrate (4.0 ml) in toluene (20 ml) was stirredunder heating at 100° C. for 1.5 hours. The reaction mixture was cooledto room temperature, and washed successively with water and brine, anddried over sodium sulfate. The solvent was evaporated under reducedpressure. The residue was purified by silica gel column chromatography(chloroform:ethyl acetate=2:1) to give3-(4-ethylphenylmethyl)-5-methyl-1H-pyrazole (3.12 g) as yellow oil.APCI-Mass m/Z 201 (M+H).

Reference Example 107 3-(4-Ethylphenylmethyl)-6-hydroxypyridine

(1) To a solution of 6-chloronicotinoyl chloride (10.0 g) andN,O-dimethylhydroxyamine hydrochloride (6.65 g) in dichloromethane (200ml) was added dropwise triethylamine (17.2 g) at 0° C. Subsequently themixture was stirred at room temperature overnight. The mixture waswashed successively with water, 5% aqueous citric acid solution, waterand brine, and then, dried over sodium sulfate. The solvent wasevaporated under reduced pressure to giveN-methoxy-N-methyl-6-chloronicotinamide (11.73 g) as pale yellow oil.APCI-Mass m/Z 201/203 (M+H).

(2) A solution of the N-methoxy-N-methyl-6-chloronicotineamide (4.2 g)in tetrahydrofuran (40 ml) was cooled to 0° C., and thereto was addeddropwise 4-ethylphenylmagnesium bromide (0.5 M tetrahydrofuran solution,55 ml). The mixture was stirred at 0° C. for 4 hours, and then at theroom temperature for 10 minutes. The reaction mixture was cooled againto 0° C., and added thereto was 10% aqueous hydrochloric acid solution.The mixture was extracted with ethyl acetate, and washed with brine anddried over sodium sulfate. The solvent was evaporated under reducedpressure, and the residue was purified by silica gel columnchromatography (hexane:ethyl acetate=20:1) to give 6-chloro-3-pyridyl4-ethylphenyl ketone (3.68 g) as colorless crystals. APCI-Mass m/Z246/248 (M+H).

(3) The above 6-chloro-3-pyridyl 4-ethylphenyl ketone (1.68 g) wasdissolved in N-methyl-2-pyrrolidinone (20 ml), and thereto were addedbenzylalcohol (815 ml) and 60% sodium hydride (275 mg). The mixture wasstirred at room temperature for 6 hours, and then at 90° C. for onehour. The reaction mixture was cooled to room temperature, and water wasadded thereto, and the mixture was extracted with ethyl acetate. Theextract was washed with water and subsequently with brine, and driedover sodium sulfate. The solvent was evaporated under reduced pressure,and the residue was purified by silica gel column chromatography(hexane:ethyl acetate=100:0-95:5) to give 6-benzyloxy-3-pyridyl4-ethylphenyl ketone (1.68 g) as colorless oil. APCI-Mass m/Z 318 (M+H).

(4) The above 6-benzyloxy-3-pyridyl 4-ethylphenyl ketone (865 mg) wasdissolved in ethylene glycol (8.5 ml), and thereto were added hydrazinehydrate (0.44 ml) and potassium hydroxide (550 mg). The mixture wasstirred under heating at 190° C. for 8 hours. The reaction mixture wascooled to room temperature, and water was added thereto, and the mixturewas extracted with ethyl acetate. The extract was washed with waterthree times, and subsequently with brine, and dried over sodium sulfate.The solvent was evaporated under reduced pressure, and the residue waspurified by silica gel column chromatography (hexane:ethylacetate=100:0-0:100) to give the desired3-(4-ethylphenylmethyl)-6-hydroroxypyridine (256 mg) as colorlesspowder. APCI-Mass m/Z 214 (M+H).

Reference Example 108 3-(4-Ethylphenylmethyl)-2-hydroxypyridine

(1) 2-Chloronicotinoyl chloride was treated in a manner similar toReference Example 107-(1), (2) and (3) to give 2-benzyloxy-3-pyridyl4-ethylphenyl ketone as colorless oil. APCI-Mass m/Z 318 (M+H).

(2) The above 2-benzyloxy-3-pyridyl 4-ethylphenyl ketone (1.69 g) wasdissolved in ethanol (15 ml), and thereto was added sodium borohydride(403 mg), and the mixture was stirred at room temperature for 3 hours.The solvent was evaporated under reduced pressure, and the residue wasdissolved in ethyl acetate. The mixture was washed with water andsuccessively with brine, and dried over sodium sulfate. The solvent wasevaporated under reduced pressure to give crude2-benzyloxy-3-pyridyl-4-ethylphenylmethanol as colorless oil, which wasused in the subsequent step without further purification.

(3) The above 2-benzyloxy-3-pyridyl-4-ethylphenylmethanol was dissolvedin methanol (10 ml), and thereto were added concentrated hydrochloricacid (1.0 ml) and 10% palladium-carbon (500 mg). The mixture was stirredat room temperature for 15 hours under hydrogen atmosphere under normalpressure. Insoluble materials were filtered off, and the solvent wasevaporated under reduced pressure. The residue was dissolved in ethylacetate, and the solution was washed with water and successively withbrine, and dried over sodium sulfate. The solvent was evaporated underreduced pressure, and the residue was purified by silica gel columnchromatography (chloroform:methanol=100:0-97:3) to give the desired3-(4-ethylphenylmethyl)-2-hydroroxypyridine (307 mg) as a pale brownsolid. APCI-Mass m/Z 214 (M+H).

Reference Example 109 3-(4-Ethylphenylmethyl)-1H-indole

(1) To a solution of indole (6.00 g) in methanol (60 ml) were addedsodium hydroxide (2.25 g) and 4-ethylbenzaldehyde (7.56 g), and themixture was stirred at room temperature for 3 days under argonatmosphere. Added thereto was water, and methanol was evaporated underreduced pressure. The residue was extracted with diethyl ether, and theextract was washed with water, and dried over magnesium sulfate. Thesolvent was evaporated under reduced pressure and the residue waspurified by silica gel column chromatography (hexane:ethylacetate=98:2-70:30) to give 4-ethylphenyl-(1H-indol-3-yl)methanol (2.10g) as a colorless solid. APCI-Mass m/Z 234 (M+H−H₂O).

(2) The above 4-ethylphenyl-(1H-indol-3-yl)methanol was treated in amanner similar to Reference Example 1-(2) to give the desired3-(4-ethylphenylmethyl)-1H-indole as colorless crystals. APCI-Mass m/Z236 (M+H).

Reference Example 110 3-(4-Ethylphenylmethyl)-1H-indazole

(1) A mixture of zinc powder (712 mg) and dibromoethane (0.04 ml) inN,N-dimethylformamide (2.5 ml) were stirred under heating at 70° C. for10 minutes under argon atmosphere. The reaction mixture was cooled toroom temperature, and chlorotrimethylsilane (0.04 ml) was added thereto,and the mixture was stirred at room temperature for 30 minutes. To theactivated zinc solution was added dropwise a solution of 4-ethylbenzylbromide (1.74 g) in N,N-dimethylformamide (10 ml) at 0° C. over a periodof 2 hours. Subsequently, the mixture was stirred at 0° C. for 2 hours,to prepare a solution of 4-ethylbenzylzinc bromide inN,N-dimethylformamide, which was used in the subsequent step withoutfurther purification.

(2) A solution of tris(dibenzylideneacetone)dipalladium (0) (167 mg) andtri(2-furyl)phosphine (135 mg) in tetrahydrofuran (20 ml) was stirred atroom temperature for 5 minutes under argon atmosphere. Thereto wereadded 1-t-butoxycarbonyl-3-iodo-1H-indazole (2.0 g) and the above4-ethylbenzylzinc bromide (N,N-dimethylformamide solution) at 0° C., andthe mixture was stirred at room temperature for 5 hours. The reactionmixture was poured into water, and the mixture was extracted withdiethyl ether. The extract was washed with water and dried overmagnesium sulfate. The solvent was evaporated under reduced pressure,and the residue was purified by silica gel column chromatography(hexane:ethyl acetate=100:0-92:8) to give1-t-butoxycarbonyl-3-(4-ethylphenylmethyl)-1H-indazole (1.37 g) ascolorless oil. APCI-Mass m/Z 337 (M+H).

(3) The above 1-t-butoxycarbonyl-3-(4-ethylphenylmethyl)-1H-indazole(1.35 g) was dissolved in methanol (15 ml), and added thereto was 28%sodium methoxide solution (methanol solution, 1.0 ml), and the mixturewas stirred at room temperature for one hour. Added thereto was anaqueous citric acid solution, and the mixture was extracted with ethylacetate. The extract was washed successively with water and brine, anddried over magnesium sulfate. The solvent was evaporated under reducedpressure, and the residue was crystallized from hexane to give thedesired 3-(4-ethylphenylmethyl)-1H-indazole (800 mg) as colorlesscrystals. APCI-Mass m/Z 237 (M+H).

Reference Example 1115-Bromo-2-methyl-1-(5-(4-trifluoromethylphenyl)-2-thienylmethyl)benzene

(1) 4-Bromobenzotrifluoride and thiophene-2-boronic acid were treated ina manner similar to Reference Example 20-(1) to give2-(4-trifluoromethylphenyl)thiophene as colorless crystals.

(2) The above 2-(4-trifluoromethylphenyl)thiophene and5-bromo-2-methylbenzaldehyde obtained in Reference Example 4 weretreated in a manner similar to Reference Example 7 to give the desired5-bromo-2-methyl-1-(5-(4-trifluoromethylphenyl)-2-thienylmethyl)benzeneas colorless crystals. APCI-Mass m/Z 425/427 (M+H+MeOH).

Reference Example 1125-Bromo-2-methyl-1-(5-(3-trifluoromethylphenyl)-2-thienylmethyl)benzene

(1) 3-Bromobenzotrifluoride and thiophene-2-boronic acid were treated ina manner similar to Reference Example 20-(1) to give2-(3-trifluoromethylphenyl)thiophene as colorless oil.

(2) The above 2-(3-trifluoromethylphenyl)thiophene and5-bromo-2-methylbenzaldehyde obtained in Reference Example 4 weretreated in a manner similar to Reference Example 7 to give the desired5-bromo-2-methyl-1-(5-(3-trifluoromethylphenyl)-2-thienylmethyl)benzeneas colorless oil.

Reference Example 113 2-(4-Ethylphenyl)thiophene

2-Bromothiophene and 4-ethylphenylboronic acid were treated in a mannersimilar to Reference Example 20-(1) to give the target compound.

Reference Example 114 2-(4-Methylphenyl)thiophene

2-Bromothiophene and 4-methylphenylboronic acid were treated in a mannersimilar to Reference Example 20-(1) to give the target compound.

Reference Example 115 2-(2,3-Dihydro-5-benzo[b]furanyl)thiophene

(1) 5,7-Dibromo-2,3-dihydrobenzo[b]furan (see WO 02/070020) (3.0 g) indiethyl ether was cooled to −78° C. under argon atmosphere, and theretowas added dropwise n-butyl lithium (2.44 M hexane solution, 5.09 ml).The mixture was stirred at the same temperature for 30 minutes, andpoured into a saturated aqueous ammonium chloride solution. The mixturewas extracted with diethyl ether, and dried over magnesium sulfate. Thesolvent was evaporated under reduced pressure to give5-bromo-2,3-dihydrobenzo[b]furan (2.0 g) as pale yellow crystals, whichwas used in the subsequent step without further purification.

(2) The above 5-bromo-2,3-dihydrobenzo[b]furan and thiophene-2-boronicacid were treated in a manner similar to Reference Example 20-(1) togive the desired 2-(2,3-dihydro-5-benzo[b]furanyl)thiophene as paleyellow crystals. APCI-Mass m/Z 203 (M+H).

Reference Example 1164-Bromo-2-(5-chloro-2-thienylmethyl)-1-fluoronaphthalene

(1) A solution of 2,2,6,6-tetramethylpiperidine (1.04 g) intetrahydrofuran (15 ml) was cooled to −78° C. under argon atmosphere,and thereto was added dropwise n-butyl lithium (1.58 M hexane solution,4.43 ml). The reaction mixture was stirred at the same temperature for30 minutes, and thereto was added dropwise a solution of1-bromo-4-fluoronaphthalene (1.50 g) in tetrahydrofuran (12 ml) at −78°C. The mixture was stirred at the same temperature for one hour, andthereto was added dropwise a solution of5-chloro-2-thiophenecarboxaldehyde (1.07 g) in tetrahydrofuran (11 ml)at −78° C. The mixture was stirred at the same temperature for 30minutes, and thereto was added a saturated aqueous ammonium chloridesolution, and the reaction mixture was extracted with ethyl acetate. Theextract was washed with brine, dried over sodium sulfate, and thesolvent was evaporated under reduced pressure. The residue was purifiedby an aminosilane-treated silica gel column chromatography (hexane:ethylacetate=3:1) to give4-bromo-1-fluoro-2-naphthyl-5-chloro-2-thienylmethanol (2.00 g) as paleyellow powder. APCI-Mass m/Z 353/355 (M+H−H₂O).

(2) The above 4-bromo-1-fluoro-2-naphthyl-5-chloro-2-thienylmethanol wastreated in a manner similar to Reference Example 1-(2) to give thedesired 4-bromo-2-(5-chloro-2-thienylmethyl)-1-fluoronaphthalene as ayellow solid.

Reference Example 1175-Bromo-2,4-dimethyl-1-(5-phenyl-2-thienylmethyl)benzene

(1) 2,4-dimethylbenzoic acid (20.0 g) was suspended in chloroform (100ml), and thereto were added oxalyl chloride (6.8 ml) andN,N-dimethylformamide (2 drops). The mixture was stirred at roomtemperature overnight. The solvent was evaporated under reducedpressure, and the residue was dissolved in methanol (200 ml). Themixture was stirred at room temperature for 3 hours. The solvent wasevaporated under reduced pressure, and the residue was dissolved inethyl acetate. The mixture was washed successively with a saturatedaqueous sodium hydrogen carbonate solution and brine, and dried oversodium sulfate. The solvent was evaporated under reduced pressure togive methyl 2,4-dimethylbenzoate as pale yellow oil, which was used inthe subsequent step without further purification.

(2) To a mixture of the above methyl 2,4-dimethylbenzoate (19.75 g) andactivated aluminum neutral oxide (120 g) was added dropwise bromine(9.25 ml) while stirring at room temperature. The mixture was stirred atroom temperature for 8 hours, and diluted with diethyl ether (1000 ml).Insoluble materials were filtered off, and washed with diethyl ether(500 ml). The combined filtrate was washed successively with 10% aqueoussodium thiosulfate solution, a saturated aqueous sodium hydrogencarbonate solution and brine. The filtrate was dried over magnesiumsulfate, and the solvent was evaporated under reduced pressure. Theresidue was crystallized from methanol (40 ml) to give methyl5-bromo-2,4-dimethylbenzoate (6.34 g) as colorless crystals. APCI-Massm/Z 243/245 (M+H).

(3) The above methyl 5-bromo-2,4-dimethylbenzoate was treated in amanner similar to Reference Example 4-(1) to give5-bromo-2,4-dimethylbenzoic acid as colorless crystals. ESI-Mass m/Z227/229 (M−H)

(4) The above 5-bromo-2,4-dimethylbenzoic acid and 2-phenylthiophenewere treated in a manner similar to Reference Example 5 to give5-bromo-2,4-dimethyl-1-(5-phenyl-2-thienylmethyl)benzene as colorlesscrystals. APCI-Mass m/Z 357/359 (M+H).

Reference Example 1185-Bromo-1-(5-phenyl-2-thienylmethyl)-2-trifluoromethylbenzene

(1) 5-Bromo-2-iodobenzoic acid (see Jorg Frahn, A.-Dieter SchluterSynthesis 1997, 1301-1304) was treated in a manner similar to ReferenceExample 117-(1) to give methyl 5-bromo-2-iodobenzoate as a brown solid.

(2) To a solution of the above methyl 5-bromo-2-iodobenzoate (4.65 g) inN-methyl-2-pyrrolydinone (20 ml) were added copper (I) bromide (235 mg)and methyl 2,2-difluoro-2-(fluorosulfonyl)acetate (2.6 ml), and themixture was stirred under heating at 120° C. for 1.5 hours. The reactionmixture was cooled, and added thereto were 10% aqueous hydrochloric acidsolution and ethyl acetate. Insoluble materials were filtered off, andan organic layer of the filtrate was washed with water for 4 times, andsubsequently washed with a saturated aqueous sodium hydrogen carbonatesolution and brine. The filtrate was dried over sodium sulfate, and thesolvent was evaporated under reduced pressure. The residue was purifiedby silica gel column chromatography (hexan:ethyl acetate=80:1) to givemethyl 5-bromo-2-trifluoromethylbenzoate (3.55 g) as colorless oil.

(3) The above methyl 5-bromo-2-trifluoromethylbenzoate was treated in amanner similar to Reference Example 4-(1) to give5-bromo-2-trifluoromethylbenzoic acid as pale brown crystals. ESI-Massm/Z 267/269 (M−H).

(4) The above 5-bromo-2-trifluoromethylbenzoic acid and2-phenylthiophene were treated in a manner similar to Reference Example5-(1) to give 5-bromo-2-trifluoromethylphenyl 5-phenyl-2-thienyl ketoneas pale yellow crystals. APCI-Mass m/Z 411/413 (M+H).

(5) To a mixed solution of the above 5-bromo-2-trifluoromethylphenyl5-phenyl-2-thienyl ketone (670 mg) in methanol (20 ml)-tetrahydrofuran(10 ml) was added sodium borohydride (62 mg), and the mixture wasstirred at room temperature for 3 hours. The solvent was evaporatedunder reduced pressure, and the residue was dissolved in chloroform (10ml)-acetonitrile (20 ml). Thereto was added triethylsilane (0.78 ml),and the mixture was cooled to 0° C. Thereto was added dropwise borontrifluoride.diethyl ether complex (0.52 ml). The mixture was stirred atroom temperature for 45 minutes, and added thereto was a saturatedaqueous sodium hydrogen carbonate solution, and the mixture wasextracted with ethyl acetate. The extract was washed with brine, anddried over sodium sulfate. The solvent was evaporated under reducedpressure, and the residue was purified by silica gel columnchromatography (hexane) to give the desired5-bromo-1-(5-phenyl-2-thienylmethyl)-2-trifluoromethylbenzene (565 mg)as colorless oil.

Reference Example 1195-Bromo-1-(5-(3-ethylphenyl)-2-thienylmethyl)-2-methylbenzene

(1) 1-Bromo-3-ethylbenzene and thiophene-2-boronic acid were treated ina manner similar to Reference Example 20-(1) to give2-(3-ethylphenyl)thiophene as a pale yellow liquid.

(2) The above 2-(3-ethylphenyl)thiophene and5-bromo-2-methylbenzaldehyde obtained in Reference Example 4 weretreated in a manner similar to Reference Example 9 to give5-bromo-1-(5-(3-ethylphenyl)-2-thienylmethyl)-2-methylbenzene as paleyellow oil. APCI-Mass m/Z 371/373 (M+H).

Reference Example 1205-Bromo-2-methyl-1-(5-(2-pyridyl)-2-thienylmethyl)benzene

(1) 2-(2-Pyridyl)thiophene and 5-bromo-2-methylbenzaldehyde obtained inReference Example 4 were treated in a manner similar to ReferenceExample 7-(1) to give5-bromo-2-methylphenyl-5-(2-pyridyl)-2-thienylmethanol as colorless oil.APCI-Mass m/Z 360/362 (M+H).

(2) A solution of the above5-bromo-2-methylphenyl-5-(2-pyridyl)-2-thienylmethanol (1.59 g) intrifluoroacetic acid (40 ml) was cooled to 0° C., and thereto were addedgradually sodium triacetoxyborohydride (4.68 g). The mixture was stirredat room temperature for one hour, and cooled again to 0° C. 10% aqueoussodium hydroxide solution was added thereto to basify the reactionmixture. The mixture was extracted with ethyl acetate, and the extractwas washed with brine, and dried over sodium sulfate. The solvent wasevaporated under reduced pressure and the residue was purified by silicagel column chromatography (hexane:ethyl acetate=3:1) to give the desired5-bromo-2-methyl-1-(5-(2-pyridyl)-2-thienylmethyl)benzene (1.38 g) as acolorless solid. APCI-Mass m/Z 344/346 (M+H).

Reference Example 121 2-(5-Fluoro-2-thienyl)thiophene

2,2′-Bithiophene (7.40 g) in tetrahydrofuran (90 ml) was cooled to −78°C. under argon atmosphere, and thereto were added dropwise n-butyllithium (1.59 M hexane solution, 28.0 ml). The mixture was stirred at 0°C. for one 30 minutes, and cooled again to −78° C. Added thereto wasN-fluorobenzenesulfonimide (15.5 g), and the mixture was graduallywarmed, and stirred at room temperature for 17 hours. The reactionmixture was poured into ice-cold water, and the solution was extractedwith hexane twice, and the extract was washed successively with waterand brine, and dried over sodium sulfate. The solvent was evaporatedunder reduced pressure and the residue was purified by silica gel columnchromatography (hexane) to give 2-(5-fluoro-2-thienyl)thiophene (5.89 g)as colorless oil.

Reference Example 1225-Bromo-2-methyl-1-(5-(3-pyridyl)-2-thienylmethyl)benzene

2-(3-Pyridyl)thiophene was treated in a manner similar to ReferenceExample 120 to give the target compound as colorless crystals. APCI-Massm/Z 344/346 (M+H).

Reference Example 1235-Bromo-1-(5-(4-methoxyphenyl)-2-thienylmethyl)-2-methylbenzene

(1) p-Bromoanisole and thiophene-2-boronic acid were treated in a mannersimilar to Reference Example 20-(1) to give 2-(4-methoxyphenyl)thiopheneas a pale yellow solid. APCI-Mass m/Z 191 (M+H).

(2) The above 2-(4-methoxyphenyl)thiophene and 4-bromo-2-methylbenzoicacid obtained in Reference Example 4-(1) were treated in a mannersimilar to Reference Example 5 to give5-bromo-1-(5-(4-methoxyphenyl)-2-thienylmethyl)-2-methylbenzene as apale yellow solid. APCI-Mass m/Z 373/375 (M+H).

Reference Example 1245-bromo-2-methyl-1-(5-(1,2-Methylenedioxybenzen-4-yl)-2-thienylmethyl)benzene

4-Bromo-1,2-(methylenedioxy)benzene was treated in a manner similar toReference Example 119 to give the target compound as colorless powder.

Reference Example 1255-Bromo-2-chloro-1-(2-(5-phenyl-2-thienyl)ethyl)benzene

(1) To a solution of 5-bromo-2-chlorobenzyl alcohol (10.66 g) in toluene(100 ml) solution were added thionyl chloride (10 ml), and pyridine (2drops), and the mixture was stirred under heating at 100° C. overnight.The solvent was evaporated under reduced pressure, and the residue wasdissolved in ethyl acetate. The solution was washed successively withwater, a 10% aqueous hydrochloric acid solution, a saturated aqueoussodium hydrogen carbonate solution and brine, and dried over sodiumsulfate. The solvent was evaporated under reduced pressure to give5-bromo-2-chlorobenzyl chloride as pale yellow crystals, which was usedin the subsequent step without further purification.

(2) The above 5-bromo-2-chlorobenzyl chloride was dissolved inacetonitrile (100 ml), and the mixture was cooled to 0° C. Added theretowas tetraethylammonium cyanide (8.8 g), and the mixture was stirred atroom temperature for 2 hours. The solvent was evaporated under reducedpressure, and the residue was dissolved in ethyl acetate. The solutionwas washed successively with water, 10% aqueous hydrochloric acidsolution, a saturated aqueous sodium hydrogen carbonate solution andbrine, and dried over sodium sulfate. The solvent was evaporated underreduced pressure to give 5-bromo-2-chlorophenylacetonitrile as a paleyellow solid, which was used in the subsequent step without furtherpurification.

(3) The above 5-bromo-2-chlorophenylacetonitrile was added to water (90ml)-sulfuric acid (75 ml), and the mixture was stirred under heating at160° C. overnight. The mixture was further diluted with water, andcooled to 0° C. The solvent was removed by decant, and the residue wasdissolved in diethyl ether. The solution was washed with water andbrine, and extracted with 10% sodium hydroxide. To the extract was addedconcentrated hydrochloric acid to make the solution acidic. Theprecipitates were collected by filtration, and purified by silica gelcolumn chromatography (chloroform) to give 5-bromo-2-chlorophenylaceticacid (6.67 g) as colorless crystals. ESI-Mass m/Z 247/249 (M−H).

(4) The above 5-bromo-2-chlorophenylacetic acid was treated in a mannersimilar to Reference Example 118-(4) and (5) to give the desired5-bromo-2-chloro-1-(2-(5-phenyl-2-thienyl)ethyl)benzene as a pale yellowsolid. APCI-Mass m/Z 377/379 (M+H).

Reference Example 1265-Bromo-1-(5-(6-fluoro-2-pyridyl)-2-thienylmethyl)2methylbenzene

(1) 2-Bromo-6-fluoropyridine and thiophene-2-boronic acid were treatedin a manner similar to Reference Example 20-(1) to give2-(6-fluoro-2-pyridyl)thiophene as yellow oil. APCI-Mass m/Z 180 (M+H).

(2) The above 2-(6-fluoro-2-pyridyl)thiophene was treated in a mannersimilar to Reference Example 120 to give the desired5-bromo-1-(5-(6-fluoro-2-pyridyl)-2-thienylmethyl)-2-methylbenzene as acolorless solid. APCI-Mass m/Z 362/364 (M+H).

Reference Example 1275-Bromo-2-methyl-1-(5-trifluoromethyl-2-thienylmethyl)benzene

2-Trifluoromethylthiophene (see Japanese Unexamined Patent PublicationNo. 2000-34239) and 5-bromo-2-methylbenzaldehyde obtained in ReferenceExample 4 were treated in a manner similar to Reference Example 7 togive the target compound as colorless oil.

Reference Example 1285-Bromo-1-(5-(5-fluoro-2-thienyl)-2-thienylmethyl)-2-methylbenzene

5-Bromo-2-methylbenzoic acid obtained in Reference Example 4-(1) and2-(5-fluoro-2-thienyl)thiophene obtained in Reference Example 121 weretreated in a manner similar to Reference Example 5 to give the targetcompound as a colorless solid. APCI-Mass m/Z 367/369 (M+H).

Reference Example 1293-Bromo-2-fluoro-6-methyl-1-(5-phenyl-2-thienylmethyl)benzene

4-Bromo-3-fluorotoluene and 5-phenyl-2-thiophenecarboxaldehyde weretreated in a manner similar to Reference Example 116 to give the targetcompound as pale blue powders. APCI-Mass m/Z 361/363 (M+H).

Reference Example 1305-Bromo-2-chloro-1-(2-phenyl-5-thiazolylmethyl)benzene

(1) 5-Bromo-2-chlorophenylacetic acid (2.0 g) obtained in ReferenceExample 125-(3) was dissolved in dichloromethane (40 ml), and theretowere added oxalyl chloride (0.77 ml) and N,N-dimethylformamide (onedrop) at 0° C. The mixture was stirred at room temperature overnight.The solvent was evaporated under reduced pressure to give5-bromo-2-chlorophenylacetyl chloride, which was used in the subsequentstep without further purification.

(2) A solution of potassium t-butoxide (1.35 g) in tetrahydrofuran (20ml) was cooled to 0° C., and thereto was added methyl isocyanoacetate(1.33 ml). Then, a solution of the above 5-bromo-2-chlorophenylacetylchloride in tetrahydrofuran (20 ml) was added thereto, and the mixturewas stirred at 0° C. for 2 hours, and then at room temperatureovernight. The mixture was cooled again to 0° C. 10% aqueous citric acidsolution was added thereto, and the mixture was extracted with ethylacetate. The extract was washed with water and brine, and dried oversodium sulfate. The solvent was evaporated under reduced pressure andthe residue was purified by silica gel column chromatography(hexane:ethyl acetate=3:1) to give5-bromo-2-chloro-1-(4-methoxycarbonyl-5-oxazolylmethyl)benzene (1.12 g)as a yellow solid. APCI-Mass m/Z 330/332 (M+H).

(3) The above5-bromo-2-chloro-1-(4-methoxycarbonyl-5-oxazolylmethyl)benzene (1.37 g)was heated under reflux in 6N aqueous hydrochloric acid solution (20 ml)overnight. The solvent was evaporated under reduced pressure, and theresidue was dissolved in methanol, and treated with carbon powder. Thecarbon powder was filtered off, and the filtrate was evaporated underreduced pressure to give crude1-(3-amino-2-oxopropyl)-5-bromo-2-chlorobenzene.hydrochloride (1.73 g)as a pale brown solid, which was used in the subsequent step withoutfurther purification. APCI-Mass m/Z 262/264 (M+H).

(4) A mixed solution of the above1-(3-amino-2-oxopropyl)-5-bromo-2-chlorobenzene.hydrochloride (1.70 g)in ethyl acetate (30 ml)-water (15 ml) was cooled to 0° C. Added theretowere benzoyl chloride (0.99 ml) and sodium hydrogen carbonate (2.39 g),and the mixture was stirred at the same temperature for 3 hours. Theorganic layer was washed with brine, and dried over sodium sulfate. Thesolvent was evaporated under reduced pressure and the residue waspurified by silica gel column chromatography (chloroform:ethylacetate=95:5) to give1-(3-benzoylamino-2-oxopropyl)-5-bromo-2-chlorobenzene (710 mg) as acolorless solid. APCI-Mass m/Z 366/368 (M+H).

(5) To a solution of the above1-(3-benzoylamino-2-oxopropyl)-5-bromo-2-chlorobenzene (710 mg) intoluene (20 ml) was added Lawesson reagent (2.35 g), and the mixture washeated under reflux for 2 hours. The reaction mixture was cooled, andthe solvent was evaporated under reduced pressure. The residue waspurified by silica gel column chromatography (hexane:ethylacetate=90:10) to give the desired5-bromo-2-chloro-1-(2-phenyl-5-thiazolylmethyl)benzene (512 mg) as acolorless solid. APCI-Mass m/Z 364/366 (M+H).

Reference Example 131 t-Butyl 5-bromo-2-chlorobenzoic acid

To a solution of 5-bromo-2-chlorobenzoic acid (11.75 g) inN,N-dimethylformamide (50 ml) was added 1,1′-carbonyldiimidazole (8.10g), and the mixture was stirred under heating at 40° C. for one hour.Thereto were added t-butanol (7.40 g) and1,8-diazabicyclo[5.4.0]undec-7-ene (7.60 g), and the mixture was furtherstirred under heating at 40° C. overnight. The mixture was diluted withdiethyl ether, and washed successively with water (3 times), 2% aqueoushydrochloric acid solution (twice), a saturated aqueous sodium hydrogencarbonate solution and brine. The mixture was dried over magnesiumsulfate, and the solvent was evaporated under reduced pressure to givet-butyl 5-bromo-2-chlorobenzoate (12.53 g) as pale yellow oil.

Reference Example 1325-Bromo-2-chloro-1-(6-ethoxybenzo[b]thiophen-2-ylmethyl)benzene

(1) A solution of5-bromo-2-chloro-1(6-methoxybenzo[b]thiophen-2-ylmethyl)benzene (2.70 g)obtained in Reference Example 46 in dichloromethane (27 ml) was cooledto 0° C. under argon atmosphere, and thereto was added dropwise borontribromide (0.83 ml). The mixture was warmed to room temperature, andstirred for 30 minutes. The mixture was basified with a saturatedaqueous sodium hydrogen carbonate solution, and subsequently, thereaction mixture was made acidic with a saturated aqueous citric acidsolution. The mixture was extracted with chloroform, and dried overmagnesium sulfate. The solvent was evaporated under reduced pressure.The residue was crystallized from chloroform-hexane to give5-bromo-2-chloro-1-(6-hydroxybenzo[b]thiophen-2-ylmethyl)benzene (2.01g) as pale green crystals. ESI-Mass m/Z 351/353 (M−H).

(2) The above5-bromo-2-chloro-1-(6-hydroxybenzo[b]thiophen-2-ylmethyl)benzene (500mg) was dissolved in N,N-dimethylformamide (5 ml), and thereto wereadded iodoethane (0.23 ml) and potassium carbonate (390 mg). The mixturewas stirred at room temperature for 2 days. Added thereto was water, andthe mixture was extracted with ethyl acetate. The extract was washedwith water and brine, and dried over magnesium sulfate. The solvent wasevaporated under reduced pressure, and the residue was purified bysilica gel column chromatography (hexane:ethyl acetate=98:2-80:20) togive the desired5-bromo-2-chloro-1-(6-ethoxybenzo[b]thiophen-2-ylmethyl)benzene (492 mg)as pale pink oil. APCI-Mass m/Z 381/383 (M+H).

Reference Example 1335-Bromo-2-chloro-3-(5-phenyl-2-thienylmethyl)thiophene

5-Bromo-2-chloro-3-thiophenecarboxylic acid (see Japanese UnexaminedPatent Publication No. 10-324632) and 2-phenylthiophene were treated ina manner similar to Reference Example 5 to give the target compound as acolorless solid. APCI-Mass m/Z 367/369 (M+H).

Reference Example 134 6-Fluoro-2-pyridylboronic acid pinacol ester

A solution of 2-bromo-6-fluoropyridine (1.0 g) in tetrahydrofuran (10ml) was cooled to −78° C. under argon atmosphere, and thereto was addeda solution of n-butyl lithium (2.59 M hexane solution, 2.24 ml) intetrahydrofuran (10 ml). The mixture was stirred at the same temperaturefor 45 minutes, and thereto was added dropwise a solution oftriisopropoxyborane (1.28 g) in tetrahydrofuran (10 ml). The mixture wasstirred at the same temperature for 2 hours, warmed, and further stirredat room temperature for one hour. Subsequently, a solution of pinacol(0.91 g) in tetrahydrofuran (10 ml) was added dropwise thereto, andstirred at room temperature for 20 minutes. Insoluble materials werefiltered off. The filtrate was extracted with 2.5% sodium hydroxide, andthe extract was cooled to 0° C., and was made weakly acidic with 2Naqueous hydrochloric acid solution. It was extracted with diethyl ether,washed with a small amount of brine, and dried over magnesium sulfate.The solvent was evaporated under reduced pressure and the residue wassolidified with hexane to give 6-fluoro-2-pyridylboronic acid pinacolester (850 mg) as a colorless solid. APCI-Mass m/Z 224 (M+H).

Reference Example 1355-Bromo-2-chloro-1-(6-phenyl-3-pyridylmethyl)benzene

(1) 5-Bromo-2-chlorobenzoic acid was treated in a manner similar toReference Example 4-(2) to giveN-methoxy-N-methyl-5-bromo-2-chlorobenzamide as a colorless solid.APCI-Mass m/Z 278/280 (M+H).

(2) The above N-methoxy-N-methyl-5-bromo-2-chlorobenzamide and2,5-dibromopyridine were treated in a manner similar to ReferenceExample 31-(4) to give 5-bromo-2-chlorophenyl 6-bromo-3-pyridyl ketoneas a pale yellow solid. APCI-Mass m/Z 374/376 (M+H).

(3) The above 5-bromo-2-chlorophenyl 6-bromo-3-pyridyl ketone andphenylboronic acid were treated in a manner similar to Reference Example20-(1) to give 5-bromo-2-chlorophenyl 6-phenyl-3-pyridyl ketone asyellow crystals. APCI-Mass m/Z 372/374 (M+H).

(4) The above 5-bromo-2-chlorophenyl 6-phenyl-3-pyridyl ketone wastreated in a manner similar to Reference Example 14-(1) to give thedesired 5-bromo-2-chloro-1-(6-phenyl-3-pyridylmethyl)benzene ascolorless crystals. APCI-Mass m/Z 358/360 (M+H).

Reference Example 1365-Bromo-2-chloro-1-(6-isopropyloxybenzo[b]thiophen-2-ylmethyl)benzene

5-Bromo-2-chloro-1-(6-hydroxybenzo[b]thiophen-2-ylmethyl)-benzeneobtained in Reference Example 132-(1) and 2-iodopropane were treated ina manner similar to Reference Example 132-(2) to give the titledcompound. APCI-Mass m/Z 395/397 (M+H).

Reference Example 1374-Bromo-1-fluoro-2-(5-(2-pyridyl)-2-thienylmethyl)naphthalene

(1) A solution of 2,2,6,6-tetramethylpiperidine (4.13 ml) intetrahydrofuran (40 ml) was cooled to −78° C. under argon atmosphere,and added dropwise thereto was n-butyl lithium (2.44 M hexane solution,10.0 ml). The mixture was stirred at the same temperature for 30minutes, and added dropwise thereto at −78° C. was a solution of1-bromo-4-fluoronaphthalene (5.0 g) in tetrahydrofuran (20 ml). Themixture was stirred at the same temperature for 1 hour, and addeddropwise thereto at −78° C. was N,N-dimethylformamide (5.16 ml). Themixture was stirred at the same temperature for 1 hour, and addedthereto was a saturated aqueous ammonium chloride solution, and themixture was extracted with ethyl acetate. The extract was washed withwater and dried over magnesium sulfate, and the solvent was evaporatedunder reduced pressure. The residue was crystallized from diisopropylether and hexane to give 4-bromo-1-fluoro-2-naphthaldehyde (4.43 g) aspale yellow crystals. APCI-Mass m/Z 267/269 (M+NH₄).

(2) The above 4-bromo-1-fluoro-2-naphthaldehyde and2-(2-pyridyl)thiophene were treated in a manner similar to ReferenceExample 120 to give the desired4-bromo-1fluoro-2-(5-(2-pyridyl)-2-thienylmethyl)naphthalene ascolorless powder. APCI-Mass m/Z 398/400 (M+H).

Reference Example 1385-Bromo-2-chloro-1-(6-ethyl-3-pyridylmethyl)benzene

(1) 5-Bromo-2-chlorophenyl 6-bromo-3-pyridyl ketone (3.2 g) fromReference Example 135-(2) was dissolved in tetrahydrofuran (80 ml), andadded thereto were triethylaluminium (1.0 M hexane solution, 9.9 ml),tetrakis(triphenylphosphine)palladium(0) (570 mg) and cerium(III)chloride (7.3 g), and the mixture was stirred at 30° C. for 1.5 hours.The reaction mixture was diluted with methanol, and the reactionsolution was basified with a saturated aqueous sodium hydrogen carbonatesolution. The insoluble materials were filtered off and, the filtratewas extracted with ethyl acetate and dried over magnesium sulfate. Thesolvent was evaporated under reduced pressure, and the residue waspurified by silica gel column chromatography (hexane:ethylacetate=99:1-85:15) to give 5-bromo-2-chlorophenyl 6-ethyl-3-pyridylketone (1.98 g) as a colorless solid. APCI-Mass m/Z 324/326 (M+H).

(2) The above 5-bromo-2-chlorophenyl 6-ethyl-3-pyridyl ketone wastreated in a manner similar to Reference Example 14-(1) to give thedesired 5-bromo-2-chloro-1-(6-ethyl-3-pyridylmethyl)benzene as acolorless oil. APCI-Mass m/Z 310/312 (M+H).

Reference Example 139 6-Ethylbenzo[b]thiophene

(1) 4-Bromo-2-fluorobenzaldehyde and ethyl thioglycolate were treated ina manner similar to Reference Example 31-(1) to give6-bromo-2-ethoxycarbonylbenzo[b]thiophene as a colorless solid.

(2) The above 6-bromo-2-ethoxycarbonylbenzo[b]thiophene was treated in amanner similar to Reference Example 138-(1) to give6-ethyl-2-ethoxycarbonylbenzo[b]thiophene as colorless oil. APCI-Massm/Z 235 (M+H).

(3) The above 6-ethyl-2-ethoxycarbonylbenzo[b]thiophene (1.26 g) wasdissolved in tetrahydrofuran (4 ml) and methanol (8 ml), and addedthereto was lithium hydroxide monohydrate (677 mg), and the mixture wasstirred at room temperature overnight. The solvent was evaporated underreduced pressure, and the residue was dissolved in water and thesolution was made acidic with a 10% aqueous hydrochloric acid solution.The precipitates were collected by filtration and washed with water togive 6-ethylbenzo[b]thiophen-2-ylcarboxylic acid (1.15 g) as colorlesscrystals. ESI-I-Mass m/Z 205 (M−H).

(4) The above 6-ethylbenzo[b]thiophen-2-ylcarboxylic acid was tread in amanner similar to Reference Example 47-(2) to give the desired6-ethylbenzo[b]thiophene as colorless oil.

Reference Example 1405-Bromo-2-chloro-1-(1-oxo-2-isoindolinylmethyl)benzene

(1) 5-Bromo-2-chlorobenzyl alcohol (3.0 g) was dissolved in toluene (30ml), and added thereto were thionyl chloride (2.35 ml) and pyridine (twodrops), and the mixture was heated under stirring at 100° C. for 2hours. The mixture was cooled, washed with a saturated aqueous sodiumhydrogen carbonate solution and brine, and dried over sodium sulfate.The solvent was evaporated under reduced pressure to give5-bromo-2-chlorobenzyl chloride (3.34 g) as pale brown oil, which wasused in the subsequent step without further purification.

(2) The above 5-bromo-2-chlorobenzyl chloride (3.34 g) was dissolved inN,N-dimethylformamide (30 ml), and added thereto was potassiumphthalimide (2.63 g), and the mixture was heated under stirring at 70°C. for 3 hours. The reaction solution was poured into water, and themixture was extracted with ethyl acetate. The extract was washed withbrine, and dried over sodium sulfate. The solvent was evaporated underreduced pressure, and the residue was crystallized from diisopropylether to give 5-bromo-2-chloro-1-(phthalimid-2-ylmethyl)benzene (3.33 g)as colorless crystals. APCI-Mass m/Z 350/352 (M+H).

(3) The above 5-bromo-2-chloro-1-(phthalimid-2-ylmethyl)-benzene (4.3 g)was dissolved in acetic acid (43 ml), and added thereto was zinc powder(8.02 g), and the mixture was heated at reflux for 3 days. The mixturewas cooled and diluted with chloroform and it was basified with anaqueous sodium hydroxide solution. The organic layer was dried oversodium sulfate, and the solvent was evaporated under reduced pressure.The residue was purified by silica gel column chromatography(hexane:ethyl acetate=6:1-4:1) to give the desired5-bromo-2-chloro-1-(1-oxo-2-isoindolinylmethyl)benzene (1.39 g) ascolorless powder. APCI-Mass m/Z 336/338 (M+H).

Reference Example 1415-Bromo-2-chloro-1-(1-phenyl-4-pyrazolylmethyl)benzene

(1) A solution of 1-phenyl-4-bromopyrazole (see M. A. Khan, et al., Can.J. Chem., (1963) 41 1540) (2.23 g) in diethyl ether (30 ml) wad cooledto −78° C. under argon atmosphere, and added dropwise thereto wasn-butyl lithium (1.59 M hexane solution, 6.9 ml). The mixture wasstirred at −20° C. to −10° C. for 5 hours, and added dropwise thereto atthe same temperature was a solution of 5-bromo-2-chlorobenzaldehyde(2.19 g) obtained in Reference Example 16-(1) in diethyl ether (30 ml).The mixture was stirred at the same temperature for 30 minutes, andadded thereto was tetrahydrofuran (30 ml), and the mixture was stirredat 0° C. for further 30 minutes. A saturated aqueous ammonium chloridesolution was added thereto, and the mixture was extracted with ethylacetate. The extract was washed with brine and dried over sodiumsulfate. The solvent was evaporated under reduced pressure, and theresidue was purified by silica gel column chromatography (hexane:ethylacetate=83:17-80:20) to give5-bromo-2-chlorophenyl-1-phenyl-4-pyrazolylmethanol (831 mg) as yellowoil. APCI-Mass m/Z 363/365 (M+H).

(2) The above 5-bromo-2-chlorophenyl-1-phenyl-4-pyrazolylmethanol wastreated in a manner similar to Reference Example 120-(2) to give thedesired 5-bromo-2-chloro-1-(1-phenyl-4-pyrazolylmethyl)benzene ascolorless powder. APCI-Mass m/Z 347/349 (M+H).

Reference Example 1425-Bromo-2-chloro-1-(6-n-propyloxybenzo[b]thiophen-2-ylmethyl)benzene

5-Bromo-2-chloro-1-(6-hydroxybenzo[b]thiophen-2-ylmethyl)benzeneobtained in Reference Example 132-(1) and 1-bromopropane were treated ina manner similar to Reference Example 132-(2) to give the targetcompound. APCI-Mass m/Z 395/397 (M+H).

Reference Example 1435-Bromo-2-chloro-1-(6-(2-fluoroethyloxy)benzo[b]thiophen-2-ylmethyl)benzene

5-Bromo-2-chloro-1-(6-hydroxybenzo[b]thiophen-2-ylmethyl)-benzeneobtained in Reference Example 132-(1) and 1-bromo-2-fluoroethane weretreated in a manner similar to Reference Example 132-(2) to give thetarget compound. APCI-Mass m/Z 399/401 (M+H).

Reference Example 144 5-Tri-n-butylstannanylthiazole

The target compound was prepared according to a method described in WO03/087104.

Reference Example 145 4-Tri-n-butylstannanylthiazole

The target compound was prepared according to a method described in WO03/087104.

Reference Example 146 Tri-n-butyl(6-methoxy-2-pyridyl)tin

The target compound was prepared according to a method described in P.Gros, et al., Synthesis (1999) 754.

Reference Example 1475-Bromo-2-chloro-1-(5-ethoxybenzo[b]thiophen-2-ylmethyl)-benzene

(1) 5-Bromo-2-chloro-1-(5-methoxybenzo[b]thiophene-2-yl methyl)benzeneobtained in Reference Example 54 was treated in a manner similar toReference Example 132-(1) to give5-bromo-2-chloro-1-(5-hydroxybenzo[b]thiophen-2-ylmethyl)-benzene.ESI-Mass m/Z 351/353 (M−H).

(2) The above5-bromo-2-chloro-1-(5-hydroxybenzo[b]thiophen-2-ylmethyl)benzene andiodoethane were treated in a manner similar to Reference Example 132-(2)to give the desired5-Bromo-2-chloro-1-(5-ethoxybenzo[b]thiophene-2-ylmethyl)-benzene.APCI-Mass m/Z 382/380 (M+H).

Reference Example 1485-Bromo-2-chloro-1-(5-(1-pyrazolyl)-2-thienylmethyl)benzene

1-(2-thienyl)pyrazole (see: Chemica Scripta (1979) 13, 157-161) and5-bromo-2-chlorobenzaldehyde obtained in Reference Example 16-(1) wereused and treated in a manner similar to Reference Example 7 to give thetitle compound as colorless solid. APCI-Mass m/z 353/355 (M+H).

Reference Example 1495-Bromo-2-chloro-1-(tert-butyldiphenylsilyloxymethyl)benzene

To a solution of 5-Bromo-2-chlorobenzylalcohol (5.15 g) inN,N-dimethylformamide (50 ml) was added diisopropylethylamine (19.8 ml)and tert-butyldiphenylchlorosilane (11.9 ml), and the mixture wasstirred at room temperature for 2 days. Under ice-cooling, to themixture was added water, and the mixture was extracted with ethylacetate. The extract was washed with successively with 0.4 M aqueoushydrochloric acid solution (twice), water, a saturated aqueous sodiumhydrogen carbonate solution and brine, and dried over magnesium sulfate.The solvent was evaporated under reduced pressure, and the residue waspurified by an aminosilane-treated silica gel column chromatography(hexane) to give5-bromo-2-chloro-1-(tert-butyldiphenylsiloxymethyl)benzene 77 (10.79 g)as colorless oil. APCI-Mass m/Z 476/478 (M+NH₄).

Reference Example 150 2-Fluoropyridin-4-boronic acid

The target compound was prepared according to a method described inTetrahedron (2002) 58, 4369-4373.

Reference Example 151 3-Difluoromethoxybenzeneboronic acid

A solution of 3-(difluoromethoxy)benzene (3.0 g) and triisopropoxyborane(2.78 g) in tetrahydrofuran (15 ml) was cooled to −78° C. under argonatmosphere, and thereto was added a solution of n-butyl lithium (1.59 Mhexane solution, 9.3 ml). The mixture was stirred at same temperaturefor 10 minutes, warmed, and further stirred at room temperatureovernight. Thereto was added 3N aqueous hydrochloric acid solution (10ml), and the mixture was stirred at room temperature for 5 minutes. Themixture was extracted with ethyl acetate. The extract was washed withbrine, and dried over sodium sulfate. The solvent was evaporated underreduced pressure. The residue was crystallized from hexane to give3-difluoromethoxybenzeneboronic acid (1.6 g) as colorless crystals.

Reference Example 152 Tri-n-butyl(2-cyano-5-pyridyl)tin

5-Bromo-2-cyanopyridine was treated in a manner similar to the methodsdescribed in European Patent Publication No. 93-00867.

Reference Example 1535-Bromo-2-chloro-1-(6-difluoromethoxybenzo[b]thiophen-2-yl-methyl)benzene

5-Bromo-2-chloro-1-(6-hydroxybenzo[b]thiophen-2-ylmethyl)-benzene (1.8g) obtained in Reference Example 132-(1) was dissolved indimethylformamide (15 ml), and added thereto were methyl2-chloro-2,2-difluoroacetate (1.63 ml) and potassium carbonate (2.28 g),and the mixture was stirred at 100° C. for 1.5 hours under argonatmosphere. The reaction mixture was acidified with 2N aqueous HClsolution and extracted with ethyl acetate. The organic layer was washedwith brine and dried over magnesium sulfate. The solvent was evaporatedunder reduced pressure, and the residue was purified by silica gelcolumn chromatography (hexane) to give5-bromo-2-chloro-1-(6-difluoromethoxybenzo[b]thiophen-2-yl-methyl)benzene(695 mg) as a colorless solid. GC-Mass m/Z 402/404 (M+).

Reference Example 1545-Bromo-1-(6-difluoromethoxybenzo[b]thiophen-2-ylmethyl)-2-methylbenzene

(1) 6-Methoxybenzo[b]thiophene (see WO 97/25033) and5-bromo-2-methylbenzaldehyde obtained in Reference Example 4 weretreated in a manner similar to Reference Example 7 to give5-Bromo-1-(6-methoxybenzo[b]thiophen-2-ylmethyl)-2-methylbenzene.APCI-Mass m/Z 347/349 (M+NH₄).

(2) The above5-bromo-1-(6-methoxybenzo[b]thiophen-2-ylmethyl)-2-methylbenzene wastreated in a manner similar to Reference Example 132-(1) to give5-Bromo-1-(6-hydroxybenzo[b]thiophen-2-ylmethyl)-2-methylbenzene.ESI-Mass m/Z 331/333 (M−H).

(3) The above5-bromo-1-(6-hydroxybenzo[b]thiophen-2-yl-methyl)-2-methylbenzene wastreated in a manner similar to Reference Example 153 to give the desired5-bromo-1-(6-difluoromethoxybenzo[b]thiophen-2-ylmethyl)-2-methylbenzeneas colorless oil. GC-Mass m/Z 382/384 (M+).

Reference Example 155 (6-Cyanopyridin-2-yl)trimethyltin

2-Bromo-6-cyanopyridine (see Japanese Patent Publication 04-253974) (1.5g) and hexamethylditin (2.69 g) were dissolved in dimethoxyethane (50ml) and thereto was added tetrakis(triphenylphosphine)palladium(0) (972mg). The mixture was refluxed for 5 hours. The solvent was evaporatedunder reduced pressure, and the residue was purified by silica gelcolumn chromatography (hexane:ethyl acetate=100:1) to give(6-cyanopyridin-2-yl)trimethyltin (980 mg) as colorless oil. APCI-Massm/Z 265/267/269 (M+H).

Reference Example 1565-Bromo-2-methyl-1-(5-(1-pyrazolyl)-2-thienylmethyl)benzene

1-(2-thienyl)pyrazole (see Chemica Scripta (1979) 13, 157-161) and5-bromo-2-methybenzaldehyde obtained in Reference Example 4 were usedand treated in a manner similar to Reference Example 7 to give the titlecompound as colorless oil. APCI-Mass m/z 333/335 (M+H).

Reference Example 1575-Bromo-1-(6-ethoxybenzo[b]thiophen-2-ylmethyl)-2-methylbenzene

5-Bromo-1-(6-hydroxybenzo[b]thiophen-2-ylmethyl)-2-methylbenzeneobtained in Reference Example 154-(2) and iodoethane were treated in amanner similar to Reference Example 132-(2) to give the desired5-bromo-1-(6-ethoxybenzo[b]thiophene-2-ylmethyl)-2-methylbenzene as paleyellow wax. APCI-Mass m/Z 361/363 (M+H).

Reference Example 1585-Bromo-1-(5-methoxybenzo[b]thiophen-2-ylmethyl)-2-methylbenzene

5-Methoxybenzo[b]thiophene (see WO 97/25033) and5-bromo-2-methylbenzaldehyde obtained in Reference Example 4 weretreated in a manner similar to Reference Example 7 to give5-bromo-1-(5-methoxybenzo[b]thiophen-2-ylmethyl)-2-methylbenzene ascolorless wax.

Reference Example 1595-Bromo-1-(5-(2-fluoroethyloxy)benzo[b]thiophen-2-ylmethyl)-2-methylbenzene

(1) 5-Bromo-1-(5-methoxybenzo[b]thiophene-2-ylmethyl)-2-methylbenzeneobtained in Reference Example 158 was treated in a manner similar toReference Example 132-(1) to give5-bromo-1-(5-hydroxybenzo[b]thiophen-2-ylmethyl)-2-methyl benzene ascolorless powder. ESI-Mass m/Z 331/333 (M−H).

(2) The above5-bromo-1-(5-hydroxybenzo[b]thiophen-2-yl-methyl)-2-methylbenzene and1-bromo-2-fluoroethane were treated in a manner similar to ReferenceExample 132-(2) to give the desired5-bromo-1-(5-(2-fluoroethyloxy)-benzo[b]thiophene-2-ylmethyl)-2-methylbenzene.

Reference Example 1605-Bromo-1-(5-ethoxybenzo[b]thiophen-2-ylmethyl)-2-methylbenzene

5-Bromo-1-(5-hydroxybenzo[b]thiophen-2-ylmethyl)-2-methylbenzeneobtained in Reference Example 159-(1) and iodoethane were treated in amanner similar to Reference Example 132-(2) to give the desired5-bromo-1-(5-ethoxybenzo[b]thiophene-2-ylmethyl)-2-methylbenzene ascolorless powder.

Reference Example 1615-Bromo-2-chloro-1-(5-(2-fluoroethyloxy)benzo[b]thiophene-2-ylmethyl)benzene

5-Bromo-2-chloro-1-(5-hydroxybenzo[b]thiophen-2-ylmethyl)-benzeneobtained in Reference Example 147-(1) and 1-bromo-2-fluoroethane weretreated in a manner similar to Example 132-(2) to give the targetcompound.

Reference Example 1625-Bromo-1-(6-(2-fluoroethyloxy)benzo[b]thiophen-2-ylmethyl)-2-methylbenzene

5-Bromo-1-(6-hydroxybenzo[b]thiophen-2-ylmethyl)-2-methyl benzeneobtained in Reference Example 154-(2) and 1-bromo-2-fluoroethane weretreated in a manner similar to Example 132-(2) to give the targetcompound as colorless wax. APCI-Mass m/Z 379/381 (M+H).

Reference Example 163 4-(Difluoromethoxy)phenylboronic acid

A solution of (4-bromophenoxy)difluoromethane (3 g) and triisopropylborate (3.42 ml) in tetrahydrofuran (15 ml) was cooled to −78° C. underargon atmosphere, and thereto was added a solution of n-butyl lithium(1.59 M hexane solution, 3.42 ml). The mixture was stirred at roomtemperature overnight. Added thereto was 6N aqueous hydrochloric acid at0° C., and the mixture was extracted with ethyl acetate. The extract waswashed with brine, and dried over magnesium sulfate. The solvent wasevaporated under reduced pressure, and the residue was triturated withcold hexane to give 4-(difluoromethoxy)phenylboronic acid (1.88 g) ascolorless solid.

Reference Example 164 Tri-n-butyl(3-methyl-5-isooxazolyl)tin

The target compound was prepared according to a method described inBioorg. & Med. Chem. Lett. (2003) 13, 4117-4120.

Reference Example 1655-Bromo-2-chloro-1-(2-trifluoromethyl-5-pyridylmethyl)benzene

(1) A solution of 5-Bromo-2-trifluoromethylpyridine (5.3 g) (see Eur. J.Org. Chem. (2003) 1159-1168) in tetrahydrofuran (70 ml) was cooled to 0°C. under argon atmosphere, and thereto was added dropwiseisopropylmagnesium chloride (1 mol/l tetrahydrofuran solution, 23.45ml). The reaction mixture was stirred at the same temperature for 2hours, and thereto was added dropwise a solution of5-bromo-2-chlorobenzaldehyde obtained in Reference Example 16-(1) (5.15g) in tetrahydrofuran (20 ml). The mixture was stirred at the sametemperature for 60 minutes, and thereto was added a saturated ammoniumchloride solution, and the reaction mixture was warmed to roomtemperature. The mixture was extracted with ethyl acetate, and theextract was dried over magnesium sulfate, and the solvent was evaporatedunder reduced pressure. The residue was purified by silica gel columnchromatography (hexane:ethyl acetate=98:2-85:15) to give(5-Bromo-2-chloro)phenyl-(2-trifluoromethyl-5-pyridyl)methanol (4.56 g)as a pale brown syrup. APCI-Mass m/Z 366/368 (M+H).

(2) The above(5-Bromo-2-chloro)phenyl-(2-trifluoromethyl-5-pyridyl)methanol (4.55 g)was dissolved in dichloromethane (50 ml) and toluene (50 ml), and addedthereto was manganese(IV) oxide (5.39 g), and the mixture was stirred atroom temperature overnight. Insoluble materials were filtered off, andthe solvent was evaporated under reduced pressure. The resultant residuewas purified by silica gel column chromatography (hexane:ethylacetate=98:2-92:8) to give (5-Bromo-2-chloro)phenyl(2-trifluoromethyl-5-pyridyl)ketone (2.64 g) as a pale yellow syrup.APCI-Mass m/Z 364/366 (M+H).

(3) The above (5-Bromo-2-chloro)phenyl(2-trifluoromethyl-5-pyridyl)ketone was treated in a manner similar toReference Example 14-(1) to give the desired5-Bromo-2-chloro-1-(2-trifluoromethyl-5-pyridylmethyl)benzene. APCI-Massm/Z 350/352 (M+H).

Reference Example 166 4-Methyl-2-tributylstannanylthiazole

A solution of n-butyl lithium (2.71 M hexane solution, 3.9 ml) intetrahydrofuran (10 ml) was cooled to −78° C. under argon atmosphere,and thereto was added dropwise a solution of 4-methylthiazole (1.0 g) intetrahydrofuran (10 ml). The mixture was stirred at same temperature forone hour and thereto was added dropwise a solution of tri-n-butyltinchloride (3.6 g) in tetrahydrofuran (10 ml). The mixture was stirred atsame temperature for 30 minutes, warmed, and further stirred at roomtemperature overnight. Thereto was added water, and the mixture wasextracted with diethyl ether. The extract was washed with brine, anddried over sodium sulfate. The solvent was evaporated under reducedpressure. The residue was purified by alumina column chromatography(hexane) to give the title compound (1.76 g) as oil. APCI-Mass m/z386/388 (M+H)

Reference Example 167 2-Fluoropyridine-3-boronic acid

The target compound was prepared according to a method described inTetrahedron (2002) 58, 3323-3328.

Reference Example 1684-Bromo-2-(5-chloro-2-thienylmethyl)-1-methoxynaphthalene

2,4-Dibromo-1-methoxynaphthalene (see Org. Lett. (2003) 5, 831) and5-chloro-2-thiophenecarboxaldehyde were treated in a manner similar toReference Example 1 to give4-Bromo-2-(5-chloro-2-thienylmethyl)-1-methoxynaphthalene.

Reference Example 1692-(2-(6-Chloro)pyridine)-4,4,5,5-tetramethyl-1,3-dioxaborolane

The target compound was prepared according to a method described inTetrahedron (2003) 59, 10043-10049.

Reference Example 170 2-Methyl-4-tri-n-butylstannanylthiazole

The target compound was prepared according to a method described inTetrahedron (2003), 9979-9984.

Reference Example 1712-(4-(2-Methyl)pyridine)-4,4,5,5-tetramethyl-1,3-dioxaborolane

The target compound was prepared according to a method described inUnited States Patent Publication No. 2003-024914.

Reference Example 172 1-(β-D-glucopyranosyl)-5-chloroindole

5-Chloro-2,3-dihydro-(1H)-indole was treated in a manner similar to themethods described in Eur. J. Med. Chem. (2004) 39, 453-458 to give thetitle compound. APCI-Mass m/z 314/316 (M+H)

Reference Example 1735-Bromo-2-chloro-1-(5-(5-fluorothiazol-2-yl)-2-thienylmethyl)benzene

(1) 2-Bromothiazole (15.0 g) and 2-thiopheneboronic acid (14.0 g) weredissolved in dimethoxyethane (150 ml). To the mixture was addedbis(triphenyl)phosphine palladium(II)dichloride (3.2 g) and 2M sodiumcarbonate (137 ml), and the mixture was refluxed under argon atmospherefor 2 hours. The mixture was cooled to room temperature, and thereaction solution was diluted with ethyl acetate, and washed with water.The organic layer was collected, dried over sodium sulfate, and thesolvent was evaporated under reduced pressure. The residue was purifiedby silica gel column chromatography (hexane:ethyl acetate=96:4) to give2-(2-thienyl)thiazole (9.87 g) as oil. APCI-Mass m/z 168 (M+H)

(2) The above compound (3.17 g) was treated in a manner similar toReference Example 121 to give 5-fluoro-2-(2-thienyl)thiazole (1.58 g) asoil. APCI-Mass m/z 186 (M+H)

(3) The above compound (1.58 g) was dissolved in chloroform (16 ml),cooled to 0° C., and thereto was added dropwise a solution of bromine(1.43 g) in chloroform (15 ml). The mixture was stirred at the sametemperature for one hour, warmed, and further stirred at roomtemperature for one hour. The reaction mixture was poured into saturatedaqueous sodium hydrogen carbonate solution, and the mixture wasextracted with chloroform. The extract was washed with 10% aqueoussodium thiosulfate solution, brine, and dried over sodium sulfate. Thesolvent was evaporated under reduced pressure. The residue was purifiedby silica gel column chromatography (hexane:ethyl acetate=97:3) to give2-(5-bromo-2-thienyl)-5-fluorothiazole (1.81 g) as a pale yellow solid.

(4) The above compound (300 mg) and 5-bromo-2-chlorobenzaldehydeobtained in Reference Example 16-(1) were used and treated in a mannersimilar to Reference Example 7 to give the desired5-bromo-2-chloro-1-(5-(5-fluorothiazol-2-yl)-2-thienylmethyl)benzene(199 mg) as a pale yellow powder.

Reference Example 174 1-(β-D-glucopyranosyl)-4-chloroindole

(1) 4-Chloroindole (3.15 g) was dissolved in trifluoroacetic acid (32ml), thereto was added triethylsilane (8.3 ml) and the mixture washeated at 50° C. with stirring for 30 minutes. The resultant mixture wascooled to room temperature, and trifluoroacetic acid was evaporatedunder reduced pressure. To the residue was added a saturated aqueoussodium hydrogen carbonate solution, and the mixture was extracted withethyl acetate twice. The organic layer was dried over magnesium sulfate,and the solvent was evaporated under reduced pressure. The residue waspurified by silica gel column chromatography (hexane:ethylacetate=100:0-80:20) to give 4-chloro-2,3-dihydro-(1H)-indole (2.89 g)as colorless oil. APCI-Mass m/z 154/156 (M+H)

(2) The above 4-chloro-2,3-dihydro-(1H)-indole was treated in a mannersimilar to described in Eur. J. Med. Chem. (2004) 39, 453-458 to givethe title compound. APCI-Mass m/z 314/316 (M+H)

Reference Example 175 1-(β-D-glucopyranosyl)-6-chloroindole

6-Chloroindole was treated in a manner similar to Reference Example 174to give the title compound. APCI-Mass m/z 314/316 (M+H).

Pharmacological Experiment

1. Assay for SGLT2 Inhibition

Test Compounds:

Compounds described in the above examples were used for the SGLT2inhibition assay.

Method:

CHOK1 cells expressing human SGLT2 were seeded in 24-well plates at adensity of 400,000 cells/well in F-12 nutrient mixture (Ham's F-12)containing 10% fetal bovine serum, 400 μg/ml Geneticin, 50 units/mlsodium penicillin G (Gibco-BRL) and 50 μg/ml streptomycin sulfate. After2 days of culture at 37° C. in a humidified atmosphere containing 5%CO₂, cells were washed once with the assay buffer (137 mM NaCl, 5 mMKCl, 1 mM CaCl₂, 1 mM MgCl₂, 50 mM Hepes, and 20 mM Tris, pH 7.4) andincubated with 250 μl of the buffer containing test compounds for 10 minat 37° C. Test compounds were dissolved in DMSO. The final concentrationof DMSO was 0.5%. The transport reaction was initiated by addition of 50μl [¹⁴C]-methyl-α-D-glucopyranoside (¹⁴C-AMG) solution (finalconcentration, 0.5 mM). After incubation for 2 hours at 37° C., theuptake was stopped by aspiration of the incubation mixture, the cellswere washed three times with ice-cold PBS. Then, cells were solubilizedwith 0.3 N NaOH and aliquots were taken for determination ofradioactivity by a liquid scintillation counter. Nonspecific AMG uptakewas defined as that which occurred in the presence of 100 μM ofphlorizin, a specific inhibitor of sodium-dependent glucosecotransporter. Specific uptake was normalized for the proteinconcentrations measured by the method of Bradford. The 50% inhibitoryconcentration (IC₅₀) values were calculated from dose-response curves byleast square method.

Results:

Results are shown in the following table:

Test Compounds IC50 (Example No.) (nM) 69 7.9 70 7.0 71 6.6 72 4.6 781.7 79 9.0 80 6.8 83 1.3 84 2.2 86 2.8 87 3.4 88 2.6 89 3.0 90 2.0 1203.4 122 8.2 123 1.4 127 1.3 130 2.4 140 5.9 142 5.6 144 4.1 145 4.0 1462.2 148 2.8 151 2.5 155 1.7 156 1.1 168 2.3 169 3.6 170 3.5 173 8.0 1767.7 177 6.7 178 5.1 179 9.8 183 9.5 185 5.6 186 5.4 187 4.3 188 1.6 1892.4 190 3.1 191 7.7 192 7.4 193 0.9 194 2.6 197 2.0 201 8.2 202 8.7 2041.4 207 0.6 208 2.4 209 3.9 210 1.0 211 1.2 212 2.6 213 5.6 214 1.5 2154.3 216 3.3 217 3.6 218 2.4 219 6.7 221 5.5 222 1.8 223 3.1 224 5.9 2251.5 226 1.2 227 3.2 228 3.6 229 2.7 230 4.0 231 3.5 232 4.0 233 2.9 2342.4 235 2.6 236 4.4 237 2.8 238 1.6 240 1.2 241 1.0 242 4.6 244 1.2 2466.4 247 2.5 248 5.1 249 4.3 250 4.2 251 3.6 252 1.4 253 1.6 254 1.7 2556.5 256 3.1 257 3.3 260 2.3 264 1.5 265 3.4 266 3.2 267 1.5 268 2.52. Urinary Glucose Excretion Test in RatsTest Compounds:

Compounds described in the above examples were used for the urinaryglucose excretion test in rats.

Methods:

6-week-old male Sprague-Dawley (SD) rats were housed in individualmetabolic cages with free access to food and water from 2 days prior tothe experiment. On the morning of the experiment, rats were administeredvehicle (0.2% carboxymethyl cellulose solution containing 0.2% Tween80)or test compounds (30 mg/kg) by oral gavage at a volume of 10 ml/kg.Then, urine of the rat was collected for 24 hours, and the urine volumewas measured. Subsequently, the glucose concentration in urine wasquantified using the enzymatic assay kit and the daily amount of glucoseexcreted in urine per individual was calculated.

Results:

Urinary glucose amount ranges are depicted by A and B. These ranges areas follows: A≧2000 mg; 2000 mg>B≧1000 mg.

Test compounds Urinary (Example No.) glucose 22 A 25 B 69 B 70 A 81 B 83A 84 A 88 B 89 B 120 A 123 A 127 A 133 B 140 B 142 A 144 B 146 A 148 B151 B 155 A 156 A 168 A 169 B 170 B 177 A 178 B 189 B 194 A 195 B 204 A207 A 208 A 209 B 210 B 214 B 216 A 217 B 221 B 223 A 226 B 227 B 228 B229 B 230 A 231 B 232 B 233 B 235 A 236 B 237 B 238 A 247 A 248 B 251 A252 B

What is claimed is:
 1. A pharmaceutical composition comprising (i) acompound of Formula (I):

wherein Ring A is

wherein R^(1a), R^(2a), R^(3a), R^(1b), R^(2b), and R^(3b) are eachindependently a hydrogen atom, a halogen atom, a hydroxy group, analkoxy group, an alkyl group, a haloalkyl group, a haloalkoxy group, ahydroxyalkyl group, an alkoxyalkyl group, an alkoxyalkoxy group, analkenyl group, an alkynyl group, a cycloalkyl group, acycloalkylidenemethyl group, a cycloalkenyl group, a cycloalkyloxygroup, a phenyl group, a phenylalkoxy group, a cyano group, a nitrogroup, an amino group, a mono- or di-alkylamino group, an alkanoylaminogroup, a carboxyl group, an alkoxycarbonyl group, a carbamoyl group, amono- or di-alkylcarbamoyl group, an alkanoyl group, analkylsulfonylamino group, a phenylsulfonylamino group, an alkylsulfinylgroup, an alkylsulfonyl group, or a phenylsulfonyl group, and Ring B is

wherein R^(4a) is a phenyl group substituted by a halogen atom, a cyanogroup, an alkyl group, a haloalkyl group, an alkoxy group, a haloalkoxygroup, an alkylenedioxy group, an alkyleneoxy group, a mono- ordi-alkylamino group; or a heterocyclyl group substituted by a halogenatom, a cyano group, an alkyl group, a haloalkyl group, an alkoxy group,or a haloalkoxy group, where the heterocyclyl group is a thienyl group,a pyridyl group, a pyrimidinyl group, a pyrazinyl group, pyrazolylgroup, a thiazolyl group, a quinolyl group, or a tetrazolyl group;R^(5a) is a hydrogen atom; X is a carbon atom; and Y is —(CH₂)_(n)—(wherein n is 1 or 2); or a pharmaceutically acceptable salt thereof;(ii) an antidiabetic agent selected from the group consisting ofinsulin, an insulin secretagogue, an insulin sensitizer, a biguanidecompound, a sulfonylurea compound, an α-glucosidase inhibitor, a PPARγagonist, a PPARα/γ dual agonist, a dipeptidyl peptidase IV inhibitor, amitiglinide compound, a nateglinide compound, a glucagon-like peptide-1,a PTP1B inhibitor, a glycogen phosphorylase inhibitor, a RXR modulator,and a glucose 6-phosphatase inhibitor; and (iii) a pharmaceuticallyacceptable carrier.
 2. The pharmaceutical composition according to claim1, wherein R^(1a), R^(2a), R^(3a), R^(1b), R^(2b), and R^(3b) are eachindependently a hydrogen atom, a halogen atom, a lower alkyl group, ahalo-lower alkyl group, a lower alkoxy group, or a phenyl group; R^(4a)is a phenyl group substituted by a halogen atom, a cyano group, a loweralkyl group, a halo-lower alkyl group, a lower alkoxy group, ahalo-lower alkoxy group, a methylenedioxy group, an ethyleneoxy group, amono- or di-lower alkylamino group; or a heterocyclyl group substitutedby a halogen atom, a cyano group, a lower alkyl group, or a lower alkoxygroup.
 3. The pharmaceutical composition according to claim 2, whereinRing A is

wherein R^(1a) is a halogen atom, a lower alkyl group, or a lower alkoxygroup, and R^(2a) and R^(3a) are hydrogen atoms; R^(4a) is a phenylgroup substituted by a substituent selected from the group consisting ofa halogen atom, a cyano group, a lower alkyl group, a halo-lower alkylgroup, a lower alkoxy group, a halo-lower alkoxy group, and a mono- ordi-lower alkylamino group; or a heterocyclyl group substituted by ahalogen atom, a cyano group, a lower alkyl group, or a lower alkoxygroup, and Y is —CH₂—.
 4. The pharmaceutical composition of claim 1,wherein R^(4a) is a phenyl group substituted by a halogen atom, a cyanogroup, a lower alkyl group, a halo-lower alkyl group, a lower alkoxygroup, or a halo-lower alkoxy group; or a heterocyclyl group substitutedby a halogen atom, a cyano group, a lower alkyl group, or a lower alkoxygroup.
 5. The pharmaceutical composition according to claim 1, whereinthe compound is represented by the following formula:

wherein R^(A) is a halogen atom, or a lower alkyl group; and Ring C is aphenyl group substituted by 1-3 substituents selected from the groupconsisting of a halogen atom, a cyano group, a lower alkyl group, ahalo-lower alkyl group, a lower alkoxy group, a halo-lower alkoxy group,a methylenedioxy group, an ethyleneoxy group, and a mono- or di-loweralkylamino group; or a heterocyclyl group substituted by 1-3substituents selected from the group consisting of a halogen atom, acyano group, a lower alkyl group, a halo-lower alkyl group, a loweralkoxy group, and a halo-lower alkoxy group; where the heterocyclylgroup is a thienyl group, a pyridyl group, a pyrimidinyl group, apyrazinyl group, pyrazolyl group, a thiazolyl group, a quinolyl group,or a tetrazolyl group; or a pharmaceutically acceptable salt thereof. 6.The pharmaceutical composition according to claim 5, wherein Ring C is aphenyl group substituted by 1-3 substituents selected from the groupconsisting of a halogen atom, a cyano group, a lower alkyl group, ahalo-lower alkyl group, a lower alkoxy group, a halo-lower alkoxy group,and a mono- or di-lower alkylamino group; or a heterocyclyl groupsubstituted by a substituent selected from the group consisting of ahalogen atom, a cyano group, a lower alkyl group, a halo-lower alkylgroup, a lower alkoxy group, and a halo-lower alkoxy group.
 7. Thepharmaceutical composition according to claim 5, wherein Ring C is aphenyl group substituted by a halogen atom, a cyano group, a lower alkylgroup, a halo-lower alkyl group, a lower alkoxy group, or a halo-loweralkoxy group; or a heterocyclyl group substituted by a halogen atom, acyano group, a lower alkyl group, or a lower alkoxy group.
 8. Thepharmaceutical composition according to claim 5, wherein Ring C is aphenyl group substituted by a halogen atom or a cyano group, or apyridyl group substituted by a halogen atom.
 9. The pharmaceuticalcomposition according to claim 1, wherein the compound is selected fromthe group consisting of:1-(β-D-glucopyranosyl)-4-methyl-3-[5-(4-fluorophenyl)-2-thienylmethyl]benzene;1-(β-D-glucopyranosyl)-4-chloro-3-[5-(3-cyanophenyl)-2-thienylmethyl]benzene;1-(β-D-glucopyranosyl)-4-chloro-3-[5-(4-cyanophenyl)-2-thienylmethyl]benzene;1-(β-D-glucopyranosyl)-4-methyl-3-[5-(6-fluoro-2-pyridyl)-2-thienylmethyl]benzene;1-(β-D-glucopyranosyl)-4-chloro-3-[5-(6-fluoro-2-pyridyl)-2-thienylmethyl]benzene;1-(β-D-glucopyranosyl)-4-methyl-3-[5-(3-difluoromethyl-phenyl)-2-thienylmethyl]benzene;1-(β-D-glucopyranosyl)-4-methyl-3-[5-(3-cyanophenyl)-2-thienylmethyl]benzene;1-(β-D-glucopyranosyl)-4-methyl-3-[5-(4-cyanophenyl)-2-thienylmethyl]benzene;and1-(β-D-glucopyranosyl)-4-chloro-3-[5-(6-fluoro-3-pyridyl)-2-thienylmethyl]benzene;or a pharmaceutically acceptable salt thereof.
 10. The pharmaceuticalcomposition according to claim 1, wherein the compound is1-(β-D-glucopyranosyl)-4-methyl-3-[5-(3-cyano-phenyl)-2-thienylmethyl]benzene,or a pharmaceutically acceptable salt thereof.
 11. The pharmaceuticalcomposition according to claim 1, wherein the compound is1-(β-D-glucopyranosyl)-4-methyl-3-[5-(4-cyano-phenyl)-2-thienylmethyl]benzene,or a pharmaceutically acceptable salt thereof.
 12. The pharmaceuticalcomposition according to claim 1, wherein the compound is1-(β-D-glucopyranosyl)-4-methyl-3-[5-(4-fluoro-phenyl)-2-thienylmethyl]benzene,or a pharmaceutically acceptable salt thereof.
 13. The pharmaceuticalcomposition according to claim 1, wherein the compound is1-(β-D-glucopyranosyl)-4-chloro-3-[5-(3-cyano-phenyl)-2-thienylmethyl]benzene,or a pharmaceutically acceptable salt thereof.
 14. The pharmaceuticalcomposition according to claim 1, wherein the compound is1-(β-D-glucopyranosyl)-4-methyl-3-[5-(6-fluoro-2-pyridyl)-2-thienylmethyl]benzene,or a pharmaceutically acceptable salt thereof.
 15. The pharmaceuticalcomposition according to claim 1, wherein the compound is1-(β-D-glucopyranosyl)-4-chloro-3-[5-(6-fluoro-2-pyridyl)-2-thienylmethyl]benzene,or a pharmaceutically acceptable salt thereof.
 16. The pharmaceuticalcomposition according to claim 1, wherein the compound is1-(β-D-glucopyranosyl)-4-chloro-3-[5-(6-fluoro-3-pyridyl)-2-thienylmethyl]benzene,or a pharmaceutically acceptable salt thereof.
 17. The pharmaceuticalcomposition according to claim 1, wherein said antidiabetic agent is abiguanide compound.
 18. The pharmaceutical composition according toclaim 1, wherein said antidiabetic agent is a dipeptidyl peptidase IVinhibitor.
 19. The pharmaceutical composition according to claim 1,wherein said antidiabetic agent is insulin.
 20. The pharmaceuticalcomposition pharmaceutical composition according to claim 1, whereinsaid antidiabetic agent is an insulin secretagogue.
 21. Thepharmaceutical composition according to claim 1, wherein saidantidiabetic agent is a sulfonylurea compound.
 22. The pharmaceuticalcomposition according the claim 1, wherein said antidiabetic agent is anα-glucosidase inhibitor.
 23. The pharmaceutical composition according toclaim 1, wherein said antiabetic agent is a PPARγ agonist.
 24. Thepharmaceutical composition according to claim 1, wherein saidantidiabetic agent is a PPARα/γ dual agonist.
 25. A pharmaceuticalcomposition comprising (i) a compound having the following structure ora pharmaceutically acceptable salt thereof:

(ii) an antidiabetic agent selected from the group consisting ofinsulin, an insulin secretagogue, an insulin sensitizer, a biguanidecompound, a sulfonylurea compound, an α-glucosidase inhibitor, a PPARγagonist, a PPARα/γ dual agonist, a dipeptidyl peptidase IV inhibitor, amitiglinide compound, a nateglinide compound, a glucagon-like peptide-1,a PTP1B inhibitor, a glycogen phosphorylase inhibitor, an RXR modulator,and a glucose 6-phosphatase inhibitor; and (iii) a pharmaceuticallyacceptable carrier.
 26. The pharmaceutical composition of claim 25,wherein the antidiabetic agent is a biguanide compound.